Advances in Nod-like receptors (NLR) biology

G Model

CGFR-802; No. of Pages 17 Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr

Survey

Advances in Nod-like receptors (NLR) biology Franc¸ois Barbe´ a, Todd Douglas a, Maya Saleh a,b,* a b

Department of Microbiology and Immunology, McGill University, Montre´al, Que´bec H3A 2B4, Canada Department of Medicine, McGill University, Montre´al, Que´bec H3G 0B1, Canada

A R T I C L E I N F O

Article history: Available online xxx Keywords: NLR Innate immunity Inflammasome Inflammation Cell death

A B S T R A C T

The innate immune system is composed of a wide repertoire of conserved pattern recognition receptors (PRRs) able to trigger inflammation and host defense mechanisms in response to endogenous or exogenous pathogenic insults. Among these, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are intracellular sentinels of cytosolic sanctity capable of orchestrating innate immunity and inflammatory responses following the perception of noxious signals within the cell. In this review, we elaborate on recent advances in the signaling mechanisms of NLRs, operating within inflammasomes or through alternative inflammatory pathways, and discuss the spectrum of their effector functions in innate immunity. We describe the progressive characterization of each NLR with associated controversies and cutting edge discoveries. ß 2014 Published by Elsevier Ltd.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nlrs that do not assemble inflammasomes. . . . . . . . . . . . . . . . . NLRA (CIITA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The NLRC sub-family . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. NOD1 and NOD2 . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. NLRC3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. NLRC5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. NLRX1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Inflammasome-forming Nlrs . . . . . . . . . . . . . . . . . . . . . . . . . . . . NLRP1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. NLRP3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Priming. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Post-translational modifications . . . . . . . . . . . . 3.2.2. Activation mechanisms . . . . . . . . . . . . . . . . . . . 3.2.3. Lysosomal destabilization . . . . . . . . . . . . . . . . . 3.2.4. Ion flux. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.5. Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.6. Binding partners of the NLRP3 inflammasome. 3.2.7. NLRP6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. NLRP7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. NLRP10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. NLRP12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. NLRC4 and NLRB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000

* Corresponding author at: McGill Life Sciences Complex, Bellini Pavilion, Rm.364, 3649 Promenade Sir-William Osler, Montre´al, Que´bec H3G0B1, Canada. Tel.: +1 514 398 2065; fax: +1 514 398 2603. E-mail address: [email protected] (M. Saleh). http://dx.doi.org/10.1016/j.cytogfr.2014.07.001 1359-6101/ß 2014 Published by Elsevier Ltd.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

2

4.

Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The innate immune system is equipped with a set of receptors, termed pattern recognition receptors (PRRs), that detect imminent dangers such as microbial invasion, environmental or endogenous noxious substances, and elicit protective responses to contain and eliminate these harmful triggers while providing the host with resistance mechanisms to tolerate damage and restore normalcy. PRRs can be classified into five main classes that include Toll-like receptors (TLRs), nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)like receptors (RLRs), absent-in-melanoma (AIM)-like receptors (ALRs) and C-type lectins (CTLs). Membrane-bound receptors survey the extracellular environment, whereas intracellular PRRs such as the NLRs ensure cytosolic sanctity by acting as critical back-up defenses and providing synergistic responses in the face of persistent danger. The presence of NLRs across different species and kingdoms of life indicates that they are an essential product of evolution, which is consistent with their conservation from plants to humans [1]. NLRs are composed of three functional domains: an N-terminal protein–protein interaction domain required for signal transduction, a central NACHT (or NBD) domain necessary for oligomerization, and a C-terminal leucine-rich repeat (LRR) that confers ligand recognition, but acts as a repressor of NLR signaling in the absence of ligand stimulation by masking the N-terminal domain [2]. Mammalian NLRs are classified according to the type of their N-terminal domain: NLRA or Class II transactivator (CIITA) contains an acidic transactivation domain, NLRBs or neuronal apoptosis inhibitor proteins (NAIPs) have a baculovirus inhibitor of apoptosis protein (IAP) repeat (BIR), NLRCs possess a caspaseactivation and recruitment domain (CARD), and NLRPs a pyrin domain (PYD) [3]. NLRX1 contains a CARD-related X effector domain of unknown function. Upon activation, NLRs scaffold large signaling complexes to mediate innate immune responses such as the induction of inflammation, autophagy or cell death. NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4 and NAIP operate through the formation of inflammasomes, signaling platforms dependent on the inflammatory protease caspase-1. On the other hand, NLRP10, NOD1, NOD2, NLRC3, NLRC5, NLRX1 and CIITA function independently of the inflammasome and mediate innate immunity through the regulation of nuclear factor-kB (NF-kB) and mitogenactivated protein kinases (MAPK) pathways, or by acting in the nucleus as transcriptional regulators.

2. Nlrs that do not assemble inflammasomes 2.1. NLRA (CIITA) Class II transactivator (CIITA) is a key regulator of MHC class I and II gene expression [4]. Its role as an MHC class II gene regulator was established when a 24 amino acid deletion splice mutant of CIITA was identified in patients with bare lymphocyte syndrome (BLS) [5]. It is constitutively expressed in cells with high MHC class II expression, such as dendritic cells (DCs) and macrophages, but is highly inducible by IFNg in many other cell types [6,7]. CIITA consists of the conventional tripartite architecture of NLRs, but also comprises three additional N-terminal domains: an acidic domain (AD), a guanosine-binding domain (GBD) and a proline/serine/threonine (PST) domain. The AD and GBD mediate

000 000 000

interactions with general transcription factors, DNA-binding transactivators and chromatin-remodeling enzymes to form an enhanceosome [8]. The GBD also contains a nuclear localization signal (NLS) that permits trafficking between the cytosol and the nucleus [6]. The PST is essential for CIITA function but its precise role is unclear. The class II transactivator function of CIITA is regulated by phosphorylation by a number of protein kinases such as PKA, PKC, glycogen synthase kinase (GSK)3 and casein kinase (CK)II on various sites within the AD, PST and LRR domains [9]. Within the enhanceosome, CIITA recruits histone acetyltransferases, such as p300 and CBP, and methyltransferases, such as CARM1, to induce transcription, and histone deacetylases, such as HDAC1, HDAC2 and HDAC5 to repress it [10,11]. Beyond this function, CIITA can also act as a general transcription factor in the TFIID basal transcription complex in response to IFNg [12]. It interacts with components of the TFIID machinery, including TATA-binding protein (TBP), TAF6, TAF9, P-TEFb and TFIIB [13,14]. Furthermore, it functionally replaces the TFIID complex component TAF1 (TATA-binding protein associated factor 1) by mediating similar auto-phosphorylation events that promote the dissociation of the inhibitory factor TAF7, allowing transcriptional initiation [15]. Thus, CIITA possesses dual functions, acting as a co-activator that nucleates an enhanceosome and a general transcription factor similar to TAF1. 2.2. The NLRC sub-family 2.2.1. NOD1 and NOD2 Nunez et al. first discovered the NLRC family members NOD1 (CARD4) and NOD2 (CARD15) in 1999 and 2001, respectively [16,17]. Two groups simultaneously reported that NOD2 is activated by muramyl dipeptide (MDP), a bacterial cell wall moiety derived from peptidoglycan [18,19]. NOD1 was shown to bind gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), also derived from bacterial peptidoglycan [20]. Interestingly, the direct binding of these receptors by their respective ligands was only recently proven. NOD1 was shown to directly interact with ie-DAP via its LRR motif [21], and biochemical and in vitro analyses showed that NOD2 directly bound to MDP [22,23]. Coulombe et al. recently characterized N-glycolyl MDP as a more potent activator of NOD2 [24]. Upon activation, NOD1 and NOD2 undergo oligomerization through their central NOD domain, enabling the recruitment of the kinase RIP2 (RICK) through a CARD-CARD homotypic interaction [25]. The essential role of RIP2 in NOD signaling was illustrated by the abrogation of NOD-dependent NF-kB activation in Rip2-deficient mice [26]. Rip2 engagement by the NOD receptors leads to its K63-linked ubiquitination by the cellular inhibitors of apoptosis proteins (cIAP)1 and cIAP2 [27], enabling the recruitment of the TAK1/TAB2/TAB3 kinase complex to RIP2. X-linked inhibitor of apoptosis protein (XIAP) similarly interacts with RIP2 and serves as a recruitment platform for the linear ubiquitination assembly complex (LUBAC) that conjugates linear ubiquitin chains to the IKK complex regulatory component NEMO to mediate NF-kB activation [28]. NOD1 and NOD2 stimulation also results in the activation of p38, c-JUN N-terminal kinase (JNK) and ERK MAPK pathways [26]. Together, these signaling pathways converge on the induction of pro-inflammatory cytokines, chemokines and antimicrobial peptides to elicit innate immunity (Fig. 1a).

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

3

Fig. 1. Activation of the NOD1 and NOD2 pathways. (A) Bacterial peptidoglycan fragments can access the cytosol via the endosomal SLC15A channel, the hPepT1 plasma membrane transporter or scavenger receptors (SR-A, MARCO). MDP and iE-DAP from peptidoglycan activates NOD1 and NOD2, respectively. Following direct or indirect peptidoglycan sensing, NOD1/2 are relocalized to the plasma membrane in complex with ERBIN, FRMPD2 or DUOX2. Activation of NOD1 or NOD2 leads to their oligomerization, promoting the recruitment of RIP2, TRAF2, TRAF5, TRAF6, cIAP1, cIAP2 and XIAP. The cIAPs conjugate K63-linked ubiquitin chains to RIP2, subsequently recruiting the TAB-TAK complex. XIAP-generated polyubiquitination of RIP2 recruit the linear ubiquitin complex (LUBAC), which then targets NEMO in the IKK complex with linear polyubiquitin that is required for maximal activation. IKKb is phosphorylated by TAK1 and in turn phosphorylates the NF-kB inhibitor IkB. Phosphorylated IkB is targeted to the proteasome for degradation following ubiquitination. p50-p65 dimers are free to enter the nucleus to induce NF-kB-dependent gene expression. TAK1 also activates the MAPK cascade, stimulating AP-1-dependent gene expression. Activation of the NODs also initiates autophagy. Several positive (green) and negative (red) regulators of this pathway have been identified, which can act at the level of NOD1/2, RIP2 or elsewhere. (B) NOD1 and NOD2 possess antiviral functions. Viral RNA can activate NOD2 and signal through the mitochondrial MAVS independently of RIP2, which induces the activation of IRF3, promoting its translocation to the nucleus to induce type I IFN. Influenza viral RNA induces mitophagy following the phosphorylation of ULK1 by RIP2.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 4

F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

2.2.1.1. Membrane recruitment. Even though the NOD receptors are firmly established as cytosolic sensors of pathogenic insults, the membrane re-localization of these receptors upon activation was reported as a required step in MDP-induced NF-kB activation. Barnich et al. generated NOD2 deletion and substitution mutants that were incapable of inducing NF-kB activation upon MDP stimulation in intestinal epithelial cells (IECs). These mutants, as well as the Crohn’s disease (CD)-associated NOD2 3020insC mutant, lack the leucine- and tryptophan-containing motif at the C-terminal end of the protein, which was proven to be required for plasma membrane association [29]. It was later shown that NOD2 is responsible for the membrane recruitment of RIP2 [30]. FERM and PDZ domain containing 2 (FRMPD2), in complex with ERBB2-interacting protein (ERBIN), were subsequently implicated in NOD2 recruitment to the basolateral membrane of polarized IECs [31,32]. NOD1 was also shown to localize to the membrane during Shigella flexneri infection, where it interacts with the tight junction-associated protein THO guanine nucleotide exchange factor 2 (ARHGEF2) [33]. Additionally, CD147, a membrane-bound regulator of cellular migration and differentiation, was reported to direct NOD2 to sites of bacterial invasion [34]. Collectively, these studies suggest that guiding NOD receptors intracellular localization is a regulatory mechanism that might favor more efficient interaction with cognate ligands. 2.2.1.2. Ligand internalization and transport. Vavricka et al. first discovered the role of the intestinal tripeptide transporter hPepT1 in MDP transport to the cytosol in a human colonic epithelial cellline [35]. This transporter was later shown to be specific to MDP [36]. Inflammatory bowel disease (IBD) patients display abnormal hPepT1 expression, and IEC-specific transgenic overexpression of hPept1 in mice exacerbated colitis induced by dextran sulfate sodium (DSS) treatment [37]. However, hPepT1-mediated MDP uptake appears to be specific to IECs, as macrophages deficient in hPept1 displayed normal MDP uptake and NOD2 activation [35–37]. Scavenger receptor A (SR-A) and Macrophage Receptor with COllagenous structure (MARCO) were also linked to rapid NOD1 and NOD2 ligand internalization [38]. Further characterization of MDP uptake mechanisms pointed to a role of clathrin- and dynamin-mediated endocytosis in this process [39]. More recently, the endosomal peptide transporters SLC15A3 and SLIC15A4 were shown to be key components of the MDP endosome-cytosol egress machinery [40–42]. Highly expressed in DCs following TLR stimulation, these proteins mediate MDP transport and signaling through recruitment of NOD2 and RIP2 to endosomes [42]. 2.2.1.3. Post-translational modifications. Post-translational modifications of NOD2 and its downstream effectors constitute an important mechanism in regulating NOD signaling and NODmediated innate immunity. Bertrand et al. reported that cIAP1 and cIAP2 were required for RIP2 K63-linked poly-ubiquitination and NOD signal transduction. cIAP1 and cIAP2-knockout mice failed to mount an immune response following administration of NOD agonists [27]. XIAP is also required for NOD signaling by ubiquitinating RIP2 and recruiting LUBAC to the NODosome [28]. Mutations in BIRC4, the gene encoding XIAP, are linked to X-linked lymphoproliferative syndrome type-2 (XLP2), a rare primary immunodeficiency associated with fatal dysregulation of the immune system [43]. Notably, a subset of XLP2 patients exhibited colitis-like symptoms [43]. Consistent with a role of XIAP in IBD, a recent exome sequencing and genotyping effort of IBD patients reported frequent occurrence of BIRC4 mutations in 4% male pediatric-onset Crohn’s disease patients [44]. Ubiquitination events also negatively regulate the NOD signaling pathway. K63-linked polyubiquitination of RIP2 by the E3 ubiquitin ligase ITCH led to downregulation of NOD2-induced NF-kB activation

[45]. Furthermore, The E3 ubiquitin ligase TRIM27 was described to negatively regulate NOD2 via K48-linked ubiquitination and subsequent proteasomal degradation [46]. Recently, a group has demonstrated that direct binding of ubiquitin chains to the CARD domains of NOD1 and NOD2 interfered with RIP2 association and downstream signaling [47]. Thus, ubiquitination plays a diverse role in NOD signaling and mediates both activation and repression via distinct mechanisms. 2.2.1.4. Regulators. Production of various transcriptional splice isoforms is a strategy adopted by the cell to intrinsically regulate the NOD2 pathway. In 2006, Rosenstiel et al. identified NOD2-S, a short isoform that encodes a protein truncated within the second CARD domain. By binding to NOD2, NOD2-S acts as an endogenous inhibitor of NOD2 oligomerization and activation. Overexpression of NOD2-S was shown to dampen NOD2-mediated signaling [48]. Kramer et al. later reported an additional alternative splice variant of NOD2, NOD2-C2, composed of the two tandem CARD domains. Unlike NOD2-S, NOD2-C2 triggered NF-kB activation independently of MDP but competed with MDP-induced activation [49]. Beyond transcriptional and post-translational modifications, regulatory proteins can modulate signaling cascades via direct binding. For example, NOD2 was shown to interact with the chaperones Hsp90 and Hsp70, which confer stabilization and protection from proteasomal degradation in the absence of stimulus [50,51]. The proteasome subunit alpha type-7 (PSMA7) was also shown to regulate NOD1 levels in a proteasomedependent manner [52]. The apoptotic protein BH3-interacting domain death agonist (BID) was identified in an siRNA screen as a potential positive regulator of NOD signaling. Co-immunoprecipitation experiments revealed that BID acted as an adaptor protein between activated RIP2 and the IKK complex [53]. Macrophages derived from Bid / mice stimulated with Nod agonists displayed decreased activation of NF-kB and ERK1/2 but intact JNK and p38 signaling, suggesting that additional factors regulated the latter MAPK pathways downstream of Nod activation. Another group reported that Nod-induced responses were not strikingly different in Biddeficient conditions [54], indicating that additional studies are needed to define the determinants of Bid involvement in the NOD pathway. Yamamoto-Furusho et al. characterized Centaurin beta1 (CENTB1), a GTPase-activating protein as a negative regulator of NOD2-mediated NF-kB activation [55]. The MAP kinase kinase kinase (MAP3K) MEKK4 was also shown to bind to RIP2 and sequester it from the NOD2 machinery [56]. Another negative regulator of NOD2 is c-Jun N-terminal kinase-binding protein 1 (JNKBP1), which acts through its WD-40 domain to bind NOD2 and prevent its oligomerization in response to MDP [57]. The inositol phosphatase SHIP-1 similarly inhibited NOD2 signaling, by preventing the association between RIP2 and XIAP [58]. Regarding the antimicrobial activity of the NOD pathway, Lipinski et al. demonstrated that reactive oxygen species (ROS) are an integral part of this process, and characterized the NADPH oxidase family member DUOX2 as a key component of the NOD pathway. The interaction between NOD2 and DUOX2 was found to promote protection against Listeria monocytogenes infections [59]. 2.2.1.5. Autophagy. Crosstalk between the NOD2 and autophagy pathways was first put forth when genome-wide association studies identified polymorphisms in the gene encoding the autophagy regulator ATG16L1 to be strongly associated with susceptibility to Crohn’s disease – a disease which has long been linked to deregulated NOD signaling [60,61]. Several studies have later shown that NOD1 and NOD2 are able to induce autophagy. In one study, NOD1 and NOD2 were shown to direct autophagy

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

to bacterial entry sites at the plasma membrane through interaction with ATGL16L1 [62]. This mechanism was reported to be RIP2- and NF-kB-independent. In parallel, Cooney et al. reported a role of NOD2-ATG16L1-mediated autophagy in bacterial handling and antigen presentation in dendritic cells (DCs). Consistent with the results of Travassos et al., they showed that DCs from CD patients expressing the NOD2 or ATG16L1 risk variants were defective in autophagy. However, unlike Travassos et al., they demonstrated a requirement for RIP2 in this process [63]. Homer et al. similarly reported that the NOD2-ATG16L1 interaction constituted part of an anti-bacterial mechanism but found that the CD-associated ATG16L1 T300A variant was impaired in MDP-induced Salmonella killing only in epithelial cells but not myeloid cells [64]. The contribution of RIP2 to NOD-induced autophagy was later confirmed by Homer et al. who demonstrated that RIP2 exerted a dual function; on one hand it stimulated p38 activation, which was required for autophagy, and on the other hand blocked the phosphatase PP2A, which acted as an inhibitor of this process [65]. More recently, the NOD2-RIP2 pathway was shown to promote mitophagy (autophagy of mitochondria) during influenza A virus infection as a means to blunt the NLRP3 inflammasome, otherwise activated by damaged mitochondria [66]. Mechanistically, the kinase activity of RIP2 was required to activate the mitophagy inducer ULK1. In addition to its role in autophagy, an autophagy-independent role for ATG16L1 in NODinduced inflammation was recently reported. It was shown that ATG16L1 inhibited NOD1 and NOD2 signaling at the level of RIP2, specifically by interfering with its polyubiquitination [67]. It is thus clear that autophagy and NOD1/2 signaling exist in a dynamic cross-regulatory state, both of which are essential for optimal homeostatic balance. 2.2.1.6. Anti-viral role of NOD2. In 2009, Sabbah et al. were first to show that NOD2 recognizes viral ssRNA and triggers activation of interferon-regulatory factor 3 (IRF3) and production of interferonbeta (IFNb). This function was reported to be independent of RIP2. Instead, NOD2 interacted with the anti-viral signaling factor mitochondrial adaptor protein (MAVS) to mediate signaling [68] (Fig. 1b). Additionally, IFNb induction by viral RNA was shown to increase the proinflammatory response to subsequent stimulation with MDP, a finding with therapeutic relevance in the context of the severity of disease in patients with respiratory syncytial virus (RSV)-induced lower respiratory tract infections [69]. More recently, NOD2 was shown to play a key role in priming an optimal CD8T cell response and adaptive immunity to influenza A virus infection, by mediating the activation and survival of DCs [70]. Together with their earlier report that RIP2 triggers mitophagy by mediating the phosphorylation of ULK1 to limit inflammasome-mediated pulmonary tissue damage [66], these results implicate the NOD2-RIP2 pathway as an important modulator of the host response to influenza infection. 2.2.1.7. Role in T cells?. The contribution of the NOD receptors to T cell function has been controversial. It was first shown that T-cell deficient mice reconstituted with Nod2-deficient T cells displayed an impaired Th-1 response following Toxoplasma gondii infection, and that Nod2 played a role in interleukin-2 (IL-2) production and CD4+ T cell proliferation and Th1 differentiation [71]. This T cellintrinsic function of NOD2 was shown to be independent of RIP2 [71]. However, these results were later disputed by Caetano et al., who reported unimpeded Th1 response following T. gondii in Nod2 deficient animals [72]. Recently, using a T cell transfer model of colitis, the expression of Nod2 in T cell was shown to be dispensable for the regulation of colitis. Although Nod2 expression was inducible following T cell receptor ligation and was increased in activated/memory T cells, its deficiency in these cells did not

5

affect the onset or progression of colitis [73]. The same group interrogated the intrinsic function of NOD2 in regulatory T cells (Treg), and demonstrated that Nod2-deficient Foxp3+ Treg cells could adequately proliferate and suppress effector T cell proliferation and function [73]. T cell-intrinsic Nod2 expression was similarly not required for CD8+ T cell responses to OVA- or influenza antigens in vitro and in vivo, respectively. However, there was a defect, albeit modest, in Nod2-deficient CD8+ T cells accumulation during infection [74]. 2.2.2. NLRC3 Conti et al. were first to clone and characterize the CATERPILAR gene CLR16.2 encoding NLRC3 (NOD3). NLRC3 was shown to be a negative regulator of T cell function potentially through its suppressive effects on the NF-kB, NFAT and AP1 pathways following T cell activation [75]. More recently, NLRC3 was also reported to blunt inflammation downstream of innate immune receptors in myeloid cells. Nlrc3 / mice injected with LPS displayed increased IL-6 levels and macrophage accumulation, which correlated with enhanced K63-ubiquitination of TRAF6 and an overt activation of NF-kB downstream of TLR signaling [76]. However, the mechanism by which NLRC3 opposes inflammation still remains obscure. Interestingly, a genetic screen in zebrafish also revealed anti-inflammatory properties of NLRC3-like protein in microglia. NLRC3-like mutants exhibited systemic inflammation and a defect in microglia development [77]. More recently, Zhang et al. described that NLRC3 blunted the activation of the cytosolic DNA sensor STING (stimulator of interferon genes) in response to intracellular DNA, cyclic di-GMP and DNA viruses (Fig. 2a). Herpessimplex virus 1 (HSV1)-infected Nlrc3 / mice displayed enhanced type I interferon production, reduced viral loads and lethality [78]. However, the precise mechanism of action of NLRC3 and the properties of its ligand(s) still remain to be elucidated. 2.2.3. NLRC5 NLRC5 is the largest member of the NLR family, and structurally resembles CIITA, notably in the NACHT and LRR motifs, suggesting functional similarity. NLRC5 contains the canonical NLR tripartite structure, but has an intriguingly long C-terminal LRR motif, as well as an N-terminal death domain (DD) [79]. Kuenzel et al. reported that human fibroblasts infected with cytomegalovirus (CMV) had increased expression of NLRC5, which positively correlated with MHC I expression. This suggested a role of NLRC5 in anti-viral immunity via MHC I transcriptional regulation [80]. Indeed, NLRC5 was found to interact with the promoter of MHC I genes, and IFNg upregulation of MHC I transcription was NLRC5dependent [79]. 2.2.3.1. Inflammation and anti-viral responses. NLRC5 was initially described in vitro to inhibit NF-kB and type I interferon pathways, as siRNA-mediated depletion of Nlrc5 in RAW264.7 cells caused increased TNFa, IL-6 and type I interferon production, which has been corroborated in a recent report [81,82]. Moreover, it was shown that LPS-induced IL-10 secretion by macrophages was promoted by NLRC5 [83], further suggesting that NLRC5 is a negative modulator of inflammation. The antiviral and antiinflammatory role of NLRC5, however, may be cell type-dependent. While bone marrow-derived macrophages and dendritic cells derived from Nlrc5 / mice produced normal levels of IFNb, IL-6 and TNFa when challenged with bacteria, RNA or DNA viruses [84], mouse embryonic fibroblasts (MEFs) and peripheral macrophages from Nlrc5 / mice displayed increased IL-6 and IFNb production following LPS treatment or vesicular stomatitis virus (VSV) infection, respectively [85]. This was confirmed in vivo as Nlrc5 / mice injected with either LPS or VSV had increased serum IL-6 and IFNb [85].

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 6

F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

Fig. 2. NLRC3 and NLRX1 signaling cascades. (A) NLRC3 acts as an inhibitor of TCR signaling by dampening AP-1-, NF-kB- and NFAT-dependent gene transcription. HSV-1, viral DNA and cyclic di-GMP trigger a STING-dependent type I IFN response from the endoplasmic reticulum that is blunted following NLRC3 binding to STING. (B) NLRX1 is activated during viral infection or during stimulation with poly I:C and has been shown to directly bind viral RNA. The subcellular localization of NLRX1 is disputed. Some groups have found it embedded in the outer mitochondrial membrane, where it interacts with MAVS to inhibit MAVS-dependent type I IFN induction, while others have found it inside the mitochondrial matrix. NLRX1 interacts with the mitochondrial TUFM to mediate ATG5-ATG12-dependent autophagy during viral infection, subsequently dampening the type I IFN response. Ubiquitination of NLRX1 downstream of TLR4 activation leads to its dissociation from TRAF6 and its binding to NEMO, which dampens the NF-kB response.

Besides this discrepancy, NLRC5 has been linked to the NLRP3 inflammasome. First, it was shown that overexpression of NLRC5 in HEK293T cells induced increased secretion of IL-1b [84]. Second, Davis et al. substantiated this link by showing that RNAi-mediated depletion of NLRC5 in human monocytic cells blunted caspase-1 activation and IL-1b and IL-18 maturation in response to a panel of NLRP3 agonists [86]. Thus, NLRC5 clearly has a diverse role in the antiviral and inflammatory responses as it seems to blunt the antiviral response while boosting inflammasome activation. 2.2.3.2. Class I transactivation. Like CIITA, NLRC5 is strongly inducible by IFNg in a STAT1-dependent manner, and is able to travel from the cytosol to the nucleus to carry out its effector function through the action of an enhanceosome [87,88]. The MHC I transactivator property of NLRC5 was reported to be dependent on an intact NBD, which supports both nuclear localization and transactivation [89]. In the nucleus, NLRC5 was seen to interact with a sequence of the MHC I promoter termed the X1 box, through its association with the transcription factors RFX5, RFXAP and RFXANK/B [87,90]. Biswas et al. recently reported that NLRC5 is necessary for both constitutive and inducible expression of MHC class I genes [91]. Consistent with this function, Nlrc5 / mice infected with the intracellular pathogen L. monocytogenes had increased bacterial loads and a defect in CD8+ T cell activation, consolidating the critical function of NLRC5 as important regulator of adaptive immunity [91]. 2.2.4. NLRX1 The role of NLRX1 is a subject of controversy. NLRX1 (also known as CLR11.2 and NOD9) was first identified to play a role in anti-viral response [92]. Through its unique association with MAVS at the outer mitochondrial membrane, which interacts with the

RIG-I-like helicase (RLH) family of cytosolic viral nucleic acid sensors, NLRX1 acted as a negative regulator of virus-induced type I interferon production in vitro [92]. Soon after, these findings were challenged, when a later report localized NLRX1 to the mitochondrial matrix, not the outer membrane [93] (Fig. 2b). Allen et al. maintained that NLRX1 is a negative regulator of type I IFN production and showed increased IFNb, STAT2 and OAS1 expression following influenza A virus infection in Nlrx1 / mice [94]. However, Nlrx1 / mice generated by two other groups exhibited normal IFNb levels following poly I:C injection [95] or influenza A virus infection [96]. A recent crystallographic characterization of NLRX1 supported a role of NLRX1 in anti-viral immunity by revealing direct interaction between the C-terminus of NLRX1 and RNA [97]. As of yet, the source of the discrepancy between laboratories in relation to NLRX1 function remains unclear. 2.2.4.1. NF-kB, JNK signaling and virus-induced autophagy. NLRX1 was also shown to negatively regulate inflammation by dampening Toll-like receptor (TLR)-mediated activation of NF-kB and JNK signaling pathways [94,98]. NLRX1 associated with TRAF6 or the IKK complex. Upon LPS stimulation, NLRX1 got rapidly ubiquitinated, dissociated from TRAF6, and interacted with the IKK complex inhibiting canonical NF-kB activation [98]. In vivo, Nlrx1 / mice challenged with LPS displayed increased plasma IL-6 levels and increased susceptibility to septic shock [94,98]. NLRX1 was also reported to act as a positive regulator of virus-induced autophagy. Following viral infection, NLRX1 associated with the mitochondrial Tu translation elongation factor (TUFM) and the autophagy-related proteins Atg5-Atg12 and Atg16L1 to form the mitochondria-immune signaling complex (MISC) [99]. NLRX1 and TUFM worked in concert to reduce cytokine production and to

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

promote virus-induced autophagy that dampens type I interferon production [99]. This suggests an alternative route by which NLRX1 dampens type I interferon production, further supporting its link to mitochondria-associated anti-viral responses. 3. Inflammasome-forming Nlrs In 2002, Martinon et al. characterized a high-molecular weight cytosolic complex that served as a platform for the recruitment of the inflammatory caspases, notably caspase-1 and caspase-5, that they dubbed the inflammasome [2]. Nlrp1 was a key component of this newly defined complex, and was the first characterized PYDcontaining NLR that could aggregate and induce IL-1b and IL-18 production. Inflammasomes are multimeric structures that are in most part composed of three main components: a sensor protein (an NLR, AIM2 or RIG-I), an adaptor (generally ASC (or PYCARD)), and caspase-1. NLR proteins that are capable of forming an inflammasome include NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4 and NAIP proteins. Stimulation of the LRR domain by cognate agonists triggers a conformational remodeling leading to the oligomerization of the sensing receptor and caspase-1 recruitment and activation. 3.1. NLRP1 NLRP1 was a key constituent of the first characterized inflammasome [2]. Mice harbor three Nlrp1 gene paralogs Nlrp1a, Nlrp1b and Nlrp1c. In 2005, Boyden and Dietriech mapped a susceptibility locus on mouse chromosome 11 to Bacillus anthracis infection. They reported that the Nlrp1b gene was highly polymorphic and was the primary mediator of mouse macrophage susceptibility to B. anthracis lethal toxin (LeTx)induced cell death [100]. Indeed, it was shown that LeTx-infected macrophages underwent a rapid highly inflammatory form of cell death dependent on caspase-1 termed pyroptosis, suggesting for the first time that Nlrp1b could activate caspase-1 in response to LeTx. This finding was confirmed in vivo recently, by the generation of Nlrp1b-deficient mice [101]. LeTx is composed of two sub-units: protective antigen (PA) and lethal factor (LF). PA is a pore-forming protein that enables the translocation of LF into the cytosol [102]. LF is a zinc metalloprotease and its catalytic activity is required for the activation of Nlrp1b. Consistently, protease-mutants of LF failed to induce pyroptosis [103]. This suggested that Nlrp1b does not directly bind to LeTx, but rather senses an event that depends on the catalytic activity of LF. Ali et al. proposed a mechanism by which LeTx-dependent inhibition of p38 and AKT signaling resulted in inflammasome activation. It involved the leakage of ATP from infected macrophages through connexin channels and subsequent stimulation of the ATPresponsive purinergic P2X7 receptor leading to inflammasome activation [104]. Levinsohn et al. demonstrated that the rat ortholog of Nlrp1 was directly cleaved by LF at the N-terminus, and that this cleavage was required for NLRP1 activation and pyroptosis [105]. The direct cleavage of murine Nlrp1b by LF was also reported to be required and sufficient for Nlrp1b activation [106] (Fig. 3). This group emitted the hypothesis that Nlrp1b, alongside other intracellular receptors, are capable of sensing ‘‘patterns of pathogenesis’’, in this context the protease activity of LeTx LF, allowing the distinction between pathogenic and harmless microbes. Among other NLRP1 activators, MDP was reported to induce caspase-1-dependent IL-1b secretion in vitro via direct binding of MDP to the LRR of NLRP1, triggering the conformational change required to recruit caspase-1 to the inflammasome [107]. NOD2 association with NLRP1 was later shown to be required for the MDP-induced activation of caspase-1 [108]. Interestingly, the

7

anti-apoptotic proteins Bcl-2 and Bcl-Xl were reported as negative regulators of MDP-induced IL-1b production, as Bcl-2 deficient macrophages stimulated with MDP displayed robust increase in IL1b production [109]. Concordantly, Gerlic et al. identified a vaccinia virus Bcl-2 homolog, F1L, which bound to and inhibited NLRP1 activation [110]. Macrophages infected with a nonfunctional F1L-bearing vaccinia virus strain displayed increased caspase-1 activation during infection [110]. The link between Bcl-2 family members and NLR regulation highlights the co-evolution of the cell death machinery and the NLR-mediated innate immunity pathways. Decrease in cellular ATP was also reported as an activating mechanism for NLRP1 [104,111]. In contrast to the ATPase domain of NLRP3, that of NLRP1 was suggested to inhibit inflammasome assembly [111]. The ability of Nlrp1 to detect cellular energy levels might provide a link between metabolism and immunity. A novel role for NLRP1 in sensing Toxoplasma infection has been recently unraveled [112,113]. Ewald et al. observed that T. gondii-induced IL-1b production in macrophages required caspase-1, the adaptor Asc and Nlrp1b [113]. Activation of Nlrp1b in this case did not require its N-terminal processing [106,113]. T. gondii-infected Nlrp1b / mice displayed increased mortality [112]. These recent findings depict a novel function of NLRP1 in controlling parasitic infections, by a mechanism that seems distinct from Anthrax LeTx-induced inflammasome activation (Fig. 3). NLRP1 protein structure is distinct from that of other NLRs. It contains a pyrin domain (PYD) on the N-terminus and a CARD on the C-terminus, as well as ZU5 and UPA internal domains (or FIIND) enabling autoproteolytic activity at a conserved SF/S motif within the FIIND [114]. This unique ability of NLRP1 to autoprocess was reported to be required for its assembly and activation [115,116]. Martinon et al. established that ASC was required for NLRP1 inflammasome assembly and function, by demonstrating that ASC depletion in LPS-primed THP1 cells abrogated caspase-1 and caspase-5 activation and IL-1b processing [2]. Similarly, rats injected with anti-ASC neutralizing antibodies in a study of traumatic brain injury showed reduced activation and processing of caspase-1 [117]. However, accumulating evidence suggests that ASC may be dispensable for the initial steps of NLRP1 inflammasome activation. Faustin et al. reconstituted the NLRP1 inflammasome, and showed that ASC enhanced but was not mandatory for NLRP1-mediated caspase-1 activation in vitro [107]. A more recent report confirmed these findings in vivo by demonstrating that ASC was required for murine NLRP1b inflammasome-mediated caspase-1 autoproteolysis, but was dispensable for Anthrax lethal toxin (LeTx)-induced IL-1b secretion and pyroptotic cell death [118]. Indeed, LPS-primed LeTx-treated macrophages derived from Asc / mice showed normal IL-1b secretion compared to cells from heterozygous mice or wild-type controls [118]. In contrast to the highly polymorphic Nlrp1b gene, Nlrp1a is conserved among mouse strains [119]. Nlrp1a expression was proposed to be under the control of the lipogenic transcription factor SREB1a [120]. However, this finding was recently contested [121]. Interestingly, using an N-ethyl-N-nitrosourea (ENU) random mutagenesis approach in mice, Masters et al. identified an Nlrp1a mutant mouse that exhibited inflammasome hyperactivation, pyroptosis of hematopoietic progenitor cells and systemic lethal inflammation [122]. These results suggest that NLRP1a might be a key sensor of hematopoietic stress and an important regulator of inflammation. 3.2. NLRP3 The NLRP3 inflammasome is arguably the most well described inflammasome to date. In 2002, gain-of-function mutations in

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 8

F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

Fig. 3. Agonists of the NLRP inflammasomes. Several of the NLRP family members have been shown to assemble into distinct inflammasomes. Anthrax lethal toxin from Bacilllus anthracis cleaves the N-terminus of NLRP1b and mediates its activation. Low cellular ATP, Toxoplasma gondii and MDP via NOD2 have also been shown to engage NLRP1 to form an inflammasome. NLRP6 has been shown to signal through an inflammasome in the context of colitis in mouse models, yet its ligand is currently unclear, but is potentially a derivative of the intestinal microbiota. Acylated lipopeptides from several bacteria engage NLRP7, and a yet unknown virulence factor from Yersinia pestis activates NLRP12. Following direct or indirect sensing of these agonists, the NLRP proteins oligomerize with ASC and pro-caspase-1, leading to activation of caspase-1 and initiation of downstream signaling. NLRP10 has been shown to potentially inhibit inflammasome activation.

late phase that involves transcriptional induction of NLRP3 by NF-

the NLRP3 gene were discovered to be associated with autoinflammatory cryopirin-associated syndromes [123,124]. NLRP3 is composed of a central NACHT domain, a C-terminal LRR and an Nterminal pyrin domain (PYD) allowing it to interact with the adaptor protein ASC to assemble an inflammasome that recruits and activates caspase-1.

priming is a matter of debate [129,130]. Whereas Zhou et al. initially proposed that ROS induced NLRP3 inflammasome activation [129], Bauernfeind et al. later showed that ROS were required for priming but dispensable for activation [130].

3.2.1. Priming Activation of the NLRP3 inflammasome requires an initial priming step (signal 1) that upregulates NLRP3 levels, followed by agonist sensing (signal 2) that induces its oligomerization and complex assembly. The priming signal was thought to rely on NFkB-mediated induction of NLRP3 gene expression downstream of TLRs, NLRs and cytokine receptors. However, increasing evidence suggest that priming can also occur independently of transcriptional upregulation of inflammasome components. For instance, in macrophages, acute stimulation of TLR4 by LPS triggers rapid priming of NLRP3 through its deubiquitination [125]. IRAK1, IRAK4 and ERK1 were implicated in such rapid non-transcriptional priming of NLRP3 [126,127]. Thus, early priming is independent of protein synthesis but requires TLR-IRAK1 signaling, followed by a

3.2.2. Post-translational modifications The observation that priming can rapidly occur independently of de novo protein synthesis suggests that more dynamic layers of control regulate inflammasome activation. Post-translational modifications represent such events that have been shown to enable inflammasome function. For instance, NLRP3 is ubiquitinated at its LRR domain in resting conditions, which prevents its oligomerization. Recently, the deubiquitinase BRCC3 was reported to be required for NLRP3 deubiquitination and subsequent activation, which is thus far the only post-translational modification reported to activate NLRP3 [131]. However, ubiquitination is a dynamic process and both NLRP3 and AIM2 inflammasomes were previously reported to be downregulated by ubiquitinationinduced autophagy and destruction [132]. Nitrosylation of NLRP3

kB [128]. The role of reactive oxygen species (ROS) in NLRP3

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

was also reported as an endogenous mechanism that blunts inflammation during persistent infection [133,134]. Phosphorylation of ASC by the kinases Syk and Jnk is an additional layer of control required for the formation of ASC specks and subsequent caspase-1 activation [135]. 3.2.3. Activation mechanisms A wide variety of unrelated ligands from endogenous and exogenous sources trigger NLRP3 activation. These include monosodium urate crystals [136], elevated ATP levels which engage the cell surface receptor P2X7R [137], asbestos, silica and other particulate matter [138,139], amyloid b aggregates [140] and pore-forming toxins [137,141] to name a few. Because these agonists are structurally diverse, it is likely that they converge on select pathways to mediate activation. Recent studies have focused

9

on unraveling common pathways triggered by the abovementioned molecules in finding a mechanism for canonical NLRP3 activation (Fig. 4). 3.2.4. Lysosomal destabilization The NLRP3 inflammasome is activated by several particulate and crystalline compounds, including the vaccine adjuvant aluminum hydroxide [142], cholesterol crystals [143] and uric acid crystals [136]. One mechanism posited for unifying the activation of NLRP3 by these compounds is the rupture of the lysosome following phagocytosis and the release of cathepsin B. 3.2.5. Ion flux Potassium and calcium fluxes across the cell membrane have been shown to enable the activation of the NLRP3 inflammasome.

Fig. 4. Signaling mechanisms of the NLRP3 inflammasome. The NLRP3 inflammasome is activated by a vast array of diverse stimuli; however, classically these were seen to converge on only a handful of pathways: potassium efflux, induced by ATP binding to P2X7R or bacterial pore-forming toxins, release of cathepsin B from the lysosome following rupture caused by particulate matter; and reactive oxygen species (ROS). Various other activating mechanisms have been described in recent years. High levels of extracellular calcium signals through CASR and GPCR6A cause a release of endoplasmic calcium stores into the cytosol, and can enter the cell via TRPM2, TRPM7 and TRPV2 ion channels. Cytosolic calcium inhibits cAMP, which itself inhibits NLRP3, and can induce mitochondrial damage. Most NLRP3 agonists induce mitochondrial dysfunction, leading to the release of large amounts of ROS, oxidized mitochondrial DNA (mtDNA) and cardiolipin, other direct NLRP3 agonists. Damaged mitochondria can be cleared via mitophagy. ROS causes the dissociation of TXNIP from TRX, allowing TXNIP to directly bind and activate NLRP3, or by inducing the deubiquitination of NLRP3. Subcellular localization of NLRP3 is currently under debate, but it has been shown to localize to the endoplasmic reticulum at rest and relocalize to the mitochondria where ASC exists following activation, in a manner that may be mediated through MAVS. Post-translational modifications regulate NLRP3 activity: deubiquitination by BRCC3 and other undefined deubiquitinases mediates NLRP3 activation, and phosphorylation of ASC by Syk and Jnk promotes inflammasome assembly, while nitrosylation inhibits inflammasome activation.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 10

F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

Petrilli et al. initially depicted a role for potassium efflux as a common trigger of both NLRP1 and NLRP3 inflammasome activation, where extracellular ATP sensing by the P2X7 receptor facilitated potassium efflux [144]. This mechanism was confirmed when a subsequent study demonstrated that blocking potassium channels with glyburide abrogated NLRP3 inflammasome activation in vitro [145]. Munoz-Planillo et al. similarly showed that a drop in cellular potassium levels was the unifying mechanism for NLRP3 activation by a number of triggers including particulate matter or bacterial toxins [146]. Increased extracellular calcium was also shown to play a role in NLRP3 activation, a process mediated by plasma membrane G-protein coupled receptor GPCR6A and calcium sensor CASR [147]. Extracellular calcium sensing triggered the release of cytosolic endoplasmic reticulum calcium stores, leading to increased intracellular calcium levels, which facilitated inflammasome assembly, in part through suppression of the NLRP3 inhibitor cyclic AMP (cAMP) [147,148]. Moreover, calcium entry through the cation channels TRPM7 and TRPV2 was suggested to regulate cytosolic calcium levels during cell volume re-adjustment following cellular swelling [149]. A recent report showed that the ROS-sensitive cation channel TRPM2 equally contributed to increased intracellular calcium levels required for NLRP3 inflammasome activation, as Trpm2 / mice were resistant to liposome-induced IL-1b production [150]. Finally, Triantafilou et al. reported that the membrane attack complex (MAC) can mediate increased cytosolic calcium leading to calcium accumulation in the mitochondrial matrix via mitochondrial calcium uniporters, and subsequently cause loss of mitochondrial transmembrane potential and NLRP3 inflammasome activation [151]. While ion flux is correlated with activation of the inflammasome, the underlying mechanism still remains unclear. One possibility could be that NLRP3 is sensitive to shifts in cellular ion concentrations, which could result in conformational change of the protein and exposure of the pyrin domain to downstream inflammasome effectors. Further investigation on the structure of NLRP3 during ionic imbalance would greatly contribute to the understanding of how NLRP3 is activated. 3.2.6. Mitochondria Many studies have implicated the mitochondria in NLRP3 inflammasome activation. The respiring organelle plausibly constitutes an adequate recruitment platform for NLRP3 oligomerization, as well as a source of various mitochondria-derived agonists that can be released if the mitochondria were compromised. A number of NLRP3 agonists were reported to trigger ROS production, suggesting that ROS might be a second messenger upstream of the NLRP3 inflammasome (reviewed in [152]). The significance of ROS in NLRP3 activation was supported by the observation that mitochondrial ROS induces the oxidation of thioredoxin, triggering its dissociation from thioredoxin-interacting partner (TXNIP) [153]. The released TXNIP directly interacts with and induces NLRP3 inflammasome activation [153]. TXNIP thereby acts as an indirect NLRP3 sensing adaptor, bridging the conserved ROS response following infection or tissue damage to activation of the inflammasome. Besides ROS, decreased mitochondrial transmembrane potential (DCM) and mitochondrial dysfunction were correlated with inflammasome activation [129]. Consistently, disrupting the mitochondrial membrane potential by blocking voltage dependent anion channels (VDAC) inhibited NLRP3 inflammasome activation [154]. Similar alterations of mitochondrial membrane potential and NLRP3 inflammasome activation were displayed by the overexpression of uncoupling protein 2 (UCP-2) in HEK293T cells, a mitochondrial inner membrane protein that mediates mitochondrial proton leakage [155]. Interestingly, a recent group identified that the microRNA miR-133a-1 targets UCP-2 [156]. miR-133a-1 overexpression in

the THP1 monocytic cell-line resulted in increased NLRP3 inflammasome activation and IL-1b production, which renders miR-133a-1 an endogenous positive regulator of the inflammasome by acting at the level of the mitochondria [156]. Release of mitochondrial damage-derived factors was reported to promote inflammasome activation. Indeed, released oxidized mitochondrial DNA (mtDNA) during apoptosis was shown to directly bind to and activate NLRP3 [157]. Mitophagy, a form of autophagy of damaged or dysfunctional mitochondria, was shown to be critical in controlling inflammasome activation [157]. A recent study demonstrated that linezolid, an oxazolidinone antibiotitic, could induce NLRP3 inflammasome activation by causing mitochondrial damage and the release of cardiolipin, which interacted with and activated NLRP3. Consistently, inhibition of cardiolipin synthesis significantly reduced NLRP3 inflammasome activation [158]. In support of a role of the mitochondria as a recruitment platform for the inflammasome, NLRP3 has been demonstrated to physically associate with respiring mitochondria through the mitochondrial adaptor MAVS [159,160]. At rest, NLRP3 is localized to the ER, while the adaptor ASC is localized to the mitochondria [161]. In response to mitochondrial damage, inactivation of sirtuin 2 enhances the levels of acetylated a-tubulin, which promotes microtubule-dependent mobilization of mitochondria to the perinuclear space bringing NLRP3 and ASC in close proximity [161]. Some reports however refuted the mitochondrial localization of NLRP3 upon activation. One study reported that activated NLRP3 remained cytosolic, with no association with any organelle [162]. Munoz-Planillo et al. similarly showed that NLRP3 did not associate with mitochondria following activation, and that ROS or a change in cell volume was not required for NLRP3 activation [146]. Promyelocytic leukemia protein (PML), which is required for IP3Rmediated ER calcium release, was required for NLRP3 activation. Lo et al. showed that PML deficiency in macrophages resulted in decreased release of mitochondrial DNA and ROS and impaired IL1b production [163]. In contrast, Dowling et al. recently reported that PML limited inflammasome activation, by interacting with ASC and retaining it inside the nucleus [164]. PML-deficient macrophages had increased ASC dimer formation in the cytosol and increased IL-1b production in response to NLRP3 activation in macrophages infected with herpes simplex virus-1 (HSV-1) or Salmonella [164]. Further investigation is thus required to resolve these contradictory results. 3.2.7. Binding partners of the NLRP3 inflammasome A wide array of interacting proteins that differentially regulate activation of the inflammasome has been identified. Strong inflammatory responses to pathogenic insults provide host protection, however sustained and uncontrolled inflammation may cause detrimental effects in the host. Endogenous repressors of the inflammasome thus represent important regulators of inflammation that prevent immunopathology. The myeloidspecific microRNA miR-223 and the Epstein–Barr virus (EBV)encoded microRNA miR-BART15 were reported to target NLRP3 mRNA causing its degradation [165,166]. CARD8 is another inhibitor of the NLPR3 pathway [167,168]. Mutant forms of NLRP3 linked to cryopyrin-associated periodic fever syndromes (CAPS) have impaired CARD8 binding, suggesting that absence of CARD8mediated modulation of NLRP3 activation might underlie the immunopathology in CAPS [168]. An additional suppressor of the NLRP3 pathway is Leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2). It suppresses caspase-1 activation through association with Flightless-1 that acts as a caspase-1 pseudosubstrate [169]. Positive regulators of the inflammasome are equally important in modulating inflammasome activation in the case of attenuated or circumvented inflammatory responses. The E3 ubiquitin ligases cIAP1 and cIAP2 were demonstrated to be required for efficient

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

inflammasome activation [170]. In contrast, XIAP indirectly blunted the inflammasome response downstream of TNF in a yet undefined mechanism involving the kinase RIP3 [171]. A recent paper found that NLRP3 is activated in response to double stranded RNA via association with the RNA helicase DHX33. siRNA depletion of DHX33 in human macrophages challenged with poly I:C, reoviral or bacterial RNA displayed decreased caspase-1 activation [172]. Protein kinase R (PKR), an RNA dependent kinase involved in antiviral defenses, was initially proposed to mediate inflammasome activation [173], but this function is controversial. While a chemical biology screen implicated PKR in pyroptosis [174], He et al. later showed that PKR was dispensable for NLRP3 activation [175]. 3.3. NLRP6 Reports on the role of NLRP6 function hitherto are now well in agreement with its role as a guardian of intestinal mucosal integrity. Initially described to have the capacity to interact with ASC and caspase-1 to form an inflammasome [176], the generation of Nlrp6-deficient mice have allowed for the characterization of the physiological relevance of NLRP6. Nlrp6 / mice are more susceptible to DSS-induced colitis, which displayed decreased serum IL-18, a key cytokine involved in intestinal wound healing following inflammasome activation [177]. Cohousing of wild-type mice with Nlrp6 / mice transferred the disease to wild-type mice, indicative of the involvement of a dysbiotic and transmissible microbiota. The expansion of certain bacterial communities in Nlrp6 / mice intestinal flora was also seen in Asc / and Casp1 / mice, which displayed similar susceptibility to colitis [178,179], thus supporting the role for NLRP6 in inflammasome formation [177]. Nlrp6 / mice displayed increased colonic CCL5 (RANTES) production, a chemokine that promotes the recruitment of inflammatory leukocytes and indirectly exacerbates inflammation. Genetic ablation of Ccl5 in Nlrp6 / mice conferred resistance to DSS-induced colitis [177]. Colonic IL-18 production by the NLRP6 inflammasome was subsequently described to participate in the regulation of the intestinal microbiota and intestinal barrier integrity. Il18-deficient mice displayed expansion of colitogenic bacterial communities and increased CCL5 production in the colon, thereby demonstrating the role of IL-18 in maintaining a healthy microbiota [177]. Moreover, Nlrp6 / mice treated with azoxymethane (AOM) and DSS displayed increased colitis-related tumorigenesis, which was associated with decreased IL-18 production in the colon and in circulation. Normand et al. subsequently demonstrated that NLRP6 ablation lead to impaired intestinal tissue repair, linking deficiency in inflammasomedependent IL-18 production to a dysregulation of the mechanisms that govern intestinal cell proliferation [180]. Recently, the role of NLRP6 in intestinal and microbial homeostasis has been substantiated in its capacity to regulate goblet cell mucus production in the gut. Indeed, Nlrp6-, Asc- and caspase-1/11-deficient mice were unable to clear enteric pathogens from the colonic mucosa, due to impaired mucus production in the large intestine [181]. Mechanistically, NLRP6 deficiency caused disruption of autophagy in intestinal goblet cells, which prevented the release of mucuscontaining granules in the lumen of the colon, therefore abrogating the formation of a protective mucus layer [181]. Together, these findings demonstrate the pivotal role of NLRP6 in the host– microbiota interface, by controlling both the composition of the microbiota and maintaining intestinal homeostasis. Aside of its implication in intestinal physiology, recent evidence have demonstrated an anti-inflammatory role for NLRP6 in response to Gram-positive and Gram-negative bacteria. Nlrp6 / mice were resistant to infection with Salmonella typhimurium, L. monocytogenes and Escherichia coli [182]. Listeria infection of macrophages

11

from Nlrp6 / mice produced aberrant levels of TNFa, IL-6 and KC, due to de-repression of MAPK and NF-kB pathways downstream of TLR stimulation [182]. Interestingly, the negative role of NLRP6 in NF-kB activation did not affect NOD1 and NOD2 signaling, suggesting an upstream role for NLRP6 in the TLR signaling pathway [182]. Taken together, NLRP6 thus appears as a negative regulator of inflammation in the context of pathogenic infection, while modulating intestinal and microbial homeostasis in the intestine. The exact activation mechanism of NLRP6 remains to be discovered (Fig. 3). 3.4. NLRP7 In 2005, NLRP7 was described as an inhibitor of the inflammasome pathway [183]. Its overexpression in HEK293T cells resulted in impaired caspase-1-mediated IL-1b production, with no apparent effect on NF-kB activation. Moreover, the N-terminal fragment of NLRP7 was sufficient to inhibit LPS-induced IL-1b production in THP1 cells, suggesting that a functional pyrin domain (PYD) was required for inhibition [183]. However, more recent evidence suggests that NLRP7 can assemble an inflammasome in response to microbial acylated lipopeptides [184] (Fig. 3). Indeed, siRNA-mediated depletion of NLRP7 or ASC in human macrophages resulted in impaired IL-1b secretion when exposed to heat-killed Mycoplasma spp., Staphylococcus aureus or Legionella pneumophilia [184]. NLRP7 overexpression resulted in the formation of a high molecular-weight complex composed of ASC and caspase-1, indicative of an NLRP7-induced inflammasome. NLRP7 and NLRP3 inflammasome-mediated production of IL-1b and IL-18 was required in blocking intracellular bacterial replication in infected THP1 cells independently of NF-kB [184]. Mutations in NLRP7 have been linked to hydatidiform moles (HMs), an abnormal pregnancy characterized by impaired embryonic development and placental hyperproliferation [185]. As of yet, it is unclear whether aberrant NLRP7 inflammasome activation is implicated in disease, though a role for NLRP7 in coordinating the secretion of cytokines via interaction with the Golgi apparatus has been suggested as a potential mechanism of pathogenesis [186]. 3.5. NLRP10 Human NLRP10 (PYNOD) was first described by Wang et al. as a negative regulator of inflammation and apoptosis. Structurally, it is composed of a NOD domain, a pyrin domain, but devoid of Cterminal LRRs [187]. The role of NLRP10 in repressing inflammation, however, has been reconsidered due to conflicting reports. Human NLRP10 inhibited caspase-1 auto-processing and ASC aggregation in HEK293T cells and overexpression of murine NLRP10 in macrophages led to decreased IL-1b production independently of these processes (Fig. 3). Moreover, NLRP10 transgenic mice were resistant to endotoxic shock [188]. However, NLRP10 was recently shown to promote IL-6 and IL-8 production in epithelial cells and primary fibroblasts infected with S. flexneri [189]. In vitro, NLRP10 interacted with multiple components of the NOD1 signaling pathway, and was proposed to act as a scaffold for the assembly of the nodosome, which potentiated the activation of NF-kB and p38 [189] (Fig. 1a). These findings suggested that NLRP10 both negatively regulates ASC-dependent inflammation, while amplifying NF-kB-derived pro-inflammatory cytokine production in response to bacterial insults. Alternatively, a role for NLRP10 in initiating adaptive immunity was also proposed. Eisenbarth et al. showed that Nlrp10 / mice displayed impaired T-cell-mediated immune responses to a variety of adjuvants [190]. Whereas Nlrp10 / mice-derived B and T cell function remained intact in vitro, impaired Th1 and Th2 responses in these mice was due to a migration defect of circulating DCs, which were unable to

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 12

F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

reach draining lymph nodes and prime naı¨ve CD4+ T cells [190]. Accordingly, Nlrp10 / mice were highly susceptible to systemic infection with Candida albicans, a fungal pathogen known to trigger a Th17 response upon infection [191]. While NLRP3-derived IL-1b and IL-18 levels were similar to those in infected WT mice, Nlrp10 / mice displayed a robust decrease in Th1 and Th17 responses, thus depicting a role for NLRP10 in orchestrating an adaptive immune response to fungal infection.

serum IL-18 and IL-1b levels [199]. Interestingly, this defect was not accompanied by impaired production of NF-kB-dependent cytokines, suggesting that NLRP12 contributes to host protection against Y. pestis in an inflammasome-dependent manner. Even though the exact nature of the ligand that bound NLRP12 was not elucidated, the activation of the NLRP12 inflammasome was dependent on a functional bacterial type 3 secretion system (T3SS) [199].

3.6. NLRP12

3.7. NLRC4 and NLRB

In 2002, Wang et al. reported a novel PYRIN-containing Apaf1like protein NLRP12 (PYPAF7, Monarch-1), which was able to promote inflammation by inducing ASC and caspase-1-dependent IL-1b production in vitro [176]. Initial in vitro assays revealed that NLRP12 acted as a positive regulator of canonical and noncanonical MHC class I expression. Accordingly, siRNA-mediated depletion of NLRP12 greatly reduced basal expression of HLA-B and HLA-G genes [192]. An alternate role for NLRP12 was subsequently defined by the same group, in which NLRP12 could modulate inflammation. Indeed, Williams et al. found that NLRP12 was a negative regulator of the NF-kB signaling pathway. Monocytes depleted of NLRP12 displayed increased production of pro-inflammatory cytokines when stimulated with agonists for TLR3 or TLR4, TNFa or infection with Mycobacterium tuberculosis. Mechanistically, it was demonstrated that NLRP12 bound to IRAK1 and inhibited its auto-phosphorylation [193]. NLRP12 was also seen to attenuate the NF-kB alternative pathway triggered by CD40 by promoting proteasomal degradation of the NF-kBinducing kinase (NIK) [194]. The ATP binding motif of NLRP12 was described to allow its association with NIK and IRAK-1 [195]. By a mechanism similar to R proteins in plants that necessitate stabilization by heat shock proteins to conduct inflammatory signals, Arthur et al. described the required interaction between NLRP12 and HSP90 in order to dampen NF-kB-dependent proinflammatory cytokine production [196]. The relevance of NLRP12 in modulating inflammation in vivo, however, was only recently uncovered. Nlrp12 / mice were highly susceptible to DSSinduced colitis and colitis-associated colorectal cancer. The overt inflammation seen in the colon of Nlrp12 / mice was due to regulatory defects in the activation of NF-kB and ERK signaling pathways in macrophages, which drove intestinal hyperplasia and subsequent increased tumor burden [197]. Zaki et al. also reported a novel role of NRLP12 in bacterial infection, in which S. typhimurium utilizes NLRP12 to modulate intestinal inflammation allowing its persistence and survival in the host. Indeed, Nlrp12 / mice were highly resistant to S. typhimurium infection and macrophages infected with S. typhimurium displayed markedly enhanced production of IL-6, KC and TNFa compared to wild-type cells. Liver homogenates of Nlrp12 / mice revealed enhanced phosphorylation of ERK and IkBa but not NF-kB p100, suggesting that NLRP12 specifically affected the canonical route of activation of NF-kB during S. typhimurium infection. Even though the activator of NLRP12 remains unknown, Salmonella LPS alone was sufficient to induce NLRP12-mediated attenuation of NF-kB [198]. The pro-inflammatory capacity of NLRP12 was initially attributed to its ability to self-oligomerize and associate with ASC and caspase-1 to promote IL-1b production in vitro [176]. The physiological relevance of NLRP12-dependent cytokine production has recently been shown to promote host protection during bacterial infection. Vladimer et al. showed that the NLRP12 inflammasome highly contributed to the production of IL-1b and IL-18 in response to Yersinia pestis infection (Fig. 3). Nlrp12 / mice infected with this bacterium exhibited increased mortality and enhanced bacterial burden, which was associated with decreased

NLRC4 (IPAF) contains an N-terminal CARD domain, enabling a direct CARD-CARD interaction with caspase-1 [200]. NLRC4 is activated by bacterial flagellin [201,202] or the rod complex of bacterial type III and IV secretion systems (T3SS, T4SS) [203]. The ability of NLRC4 to recognize flagellin and T3SS components was linked to an interaction between NLRC4 and another class of NOD proteins known as NAIPs (NLRB). Murine NAIP5 and NAIP6 recognize flagellin and NAIP2 recognizes T3SS rod proteins such as PrgJ and Mxil, respectively, which then activate NLRC4 [200,204] (Fig. 5). Thethorey et al. recently found that ligand detection by NAIPs is mediated by an internal region composed of NBDassociated a-helical domains, and not by the LRR domain [205]. NAIP recognition of bacterial moieties represents one of the first instances of direct ligand binding to an NLR protein and provides insights into the mechanisms of inflammasome activation. A

Fig. 5. Sensing of bacterial infection by NAIPs and the NLRC4 inflammasome. The NLRC4 inflammasome is activated by bacterial flagellin and the rod proteins of bacterial type III and IV secretion systems (T3SS, T4SS) within the cytosol. Direct recognition of flagellin by NAIP5 and NAIP6, and rod proteins, such as Mxil, by NAIP2 initiate the activation of NLRC4 inflammasome. While ASC has been shown to partially promote the NLCR4 inflammasome, it is not absolutely required. Phsophorylation of NLRC4 by PKCd has been suggested to be essential for its activation, although this remains to be fully characterized.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

recent report found that NAIP1 in mice recognizes the needle component of some T3SS [206]. In humans, a single NAIP exists, which functionally resembles murine NAIP1 as it recognizes the needle protein of T3SS of the bacterium Chromobacterium violaceum [207]. PKCd phosphorylation of NLRC4 on Ser533 during S. typhimurium infection of macrophages was reported to be required for inflammasome activation, as macrophages expressing a NLRC4 Ser533 mutant did not display ASC specks, produced reduced IL-1b levels and failed to induce pyroptotic cell death following infection [208]. Interestingly, NLRC4 inflammasome activation through recognition of the Shigella T3SS inner rod protein Mxil by NAIP2 did not require PKCd-mediated phopshorylation of NLRC4 [209]. These findings suggest that activation of NLRC4 can occur independently of this phopshorylation event. 4. Conclusion and future perspectives Collectively, a large number of studies have supported the role of NLRs as pivotal drivers of innate immunity. These are cytosolic receptors capable of regulating inflammation by triggering the assembly of inflammasomes and by modulating the NF-kB, MAPK and IRF signaling pathways. The capability of some NLRs to function independently of these inflammatory pathways, namely by the transcriptional upregulation of MHC molecules, broadens the implication of these receptors in innate immunity. However, mechanisms governing direct ligand binding and activation of most NLRs still remain elusive. In light of this, investigations centered on the identification of interacting partners and upstream modulators of NLRs are needed. Furthermore, tissue-specific functions of NLRs and their regulation by environmental signals require further exploration using next-generation mouse models in which tissue-specific deletion can be achieved in defined environmental conditions. Mouse genetic background and microbiota variability among different facilities might underlie some of the variability described in the field and need to be carefully controlled for in the future. Acknowledgments This work was supported by grants from the Canadian Institutes for Health Research (MOP-82801) and the Burroughs Wellcome Fund to M.S. who is a Fonds de Recherche en Sante´ du Que´bec (FRSQ) Senior Investigator and a McGill University William Dawson Scholar. References [1] Bryant CE, Monie TP. Mice, men and the relatives: cross-species studies underpin innate immunity. Open Biol 2012;2:120015. [2] Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417–26. [3] Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, et al. The NLR gene family: a standard nomenclature. Immunity 2008;28:285–7. [4] Martin BK, Chin KC, Olsen JC, Skinner CA, Dey A, Ozato K, et al. Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 1997;6:591–600. [5] Steimle V, Otten LA, Zufferey M, Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 1993;75:135–46. [6] Spilianakis C, Papamatheakis J, Kretsovali A. Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Mol Cell Biol 2000;20:8489–98. [7] Nagarajan UM, Bushey A, Boss JM. Modulation of gene expression by the MHC class II transactivator. J Immunol 2002;169:5078–88. [8] Sisk TJ, Gourley T, Roys S, Chang CH. MHC class II transactivator inhibits IL-4 gene transcription by competing with NF-AT to bind the coactivator CREB binding protein (CBP)/p300. J Immunol 2000;165:2511–7. [9] Wu X, Kong X, Luchsinger L, Smith BD, Xu Y. Regulating the activity of class II transactivator by posttranslational modifications: exploring the possibilities. Mol Cell Biol 2009;29:5639–44.

13

[10] Zika E, Fauquier L, Vandel L, Ting JP. Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression. Proc Natl Acad Sci USA 2005;102: 16321–26. [11] Wright KL, Ting JP. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol 2006;27:405–12. [12] Howcroft TK, Raval A, Weissman JD, Gegonne A, Singer DS. Distinct transcriptional pathways regulate basal and activated major histocompatibility complex class I expression. Mol Cell Biol 2003;23:3377–91. [13] Mahanta SK, Scholl T, Yang FC, Strominger JL. Transactivation by CIITA, the type II bare lymphocyte syndrome-associated factor, requires participation of multiple regions of the TATA box binding protein. Proc Natl Acad Sci USA 1997;94:6324–9. [14] Kanazawa S, Okamoto T, Peterlin BM. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity 2000;12:61–70. [15] Soe KC, Devaiah BN, Singer DS. Transcriptional coactivator CIITA, a functional homolog of TAF1, has kinase activity. Biochim Biophys Acta 2013;1829: 1184–90. [16] Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem 1999;274: 14560–67. [17] Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001;411:603–6. [18] Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, et al. Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science 2003;300:1584–7. [19] Tanabe T, Chamaillard M, Ogura Y, Zhu L, Qiu S, Masumoto J, et al. Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J 2004;23:1587–97. [20] Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003;4:702–7. [21] Laroui H, Yan Y, Narui Y, Ingersoll SA, Ayyadurai S, Charania MA, et al. L -Ala-gamma-D -Glu-meso-diaminopimelic acid (DAP) interacts directly with leucine-rich region domain of nucleotide-binding oligomerization domain 1, increasing phosphorylation activity of receptor-interacting serine/threonine-protein kinase 2 and its interaction with nucleotidebinding oligomerization domain 1. J Biol Chem 2011;286:31003–13. [22] Grimes CL, Ariyananda Lde Z, Melnyk JE, O’Shea EK. The innate immune protein Nod2 binds directly to MDP, a bacterial cell wall fragment. J Am Chem Soc 2012;134:13535–37. [23] Mo J, Boyle JP, Howard CB, Monie TP, Davis BK, Duncan JA. Pathogen sensing by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is mediated by direct binding to muramyl dipeptide and ATP. J Biol Chem 2012;287:23057–67. [24] Coulombe F, Divangahi M, Veyrier F, de Leseleuc L, Gleason JL, Yang Y, et al. Increased NOD2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med 2009;206:1709–16. [25] Tattoli I, Travassos LH, Carneiro LA, Magalhaes JG, Girardin SE. The nodosome: Nod1 and Nod2 control bacterial infections and inflammation. Semin Immunopathol 2007;29:289–301. [26] Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307:731–4. [27] Bertrand MJ, Doiron K, Labbe K, Korneluk RG, Barker PA, Saleh M. Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 2009;30:789–801. [28] Damgaard RB, Nachbur U, Yabal M, Wong WW, Fiil BK, Kastirr M, et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell 2012;46:746–58. [29] Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK. Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramyl dipeptide recognition. J Cell Biol 2005;170:21–6. [30] Lecine P, Esmiol S, Metais JY, Nicoletti C, Nourry C, McDonald C, et al. The NOD2-RICK complex signals from the plasma membrane. J Biol Chem 2007;282:15197–207. [31] Kufer TA, Kremmer E, Banks DJ, Philpott DJ. Role for erbin in bacterial activation of Nod2. Infect Immun 2006;74:3115–24. [32] Lipinski S, Grabe N, Jacobs G, Billmann-Born S, Till A, Hasler R, et al. RNAi screening identifies mediators of NOD2 signaling: implications for spatial specificity of MDP recognition. Proc Natl Acad Sci USA 2012;109: 21426–31. [33] Fukazawa A, Alonso C, Kurachi K, Gupta S, Lesser CF, McCormick BA, et al. GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors. PLoS Pathog 2008;4:e1000228. [34] Till A, Rosenstiel P, Brautigam K, Sina C, Jacobs G, Oberg HH, et al. A role for membrane-bound CD147 in NOD2-mediated recognition of bacterial cytoinvasion. J Cell Sci 2008;121:487–95. [35] Vavricka SR, Musch MW, Chang JE, Nakagawa Y, Phanvijhitsiri K, Waypa TS, et al. hPepT1 transports muramyl dipeptide, activating NF-kappaB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology 2004;127:1401–9.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 14

F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

[36] Ismair MG, Vavricka SR, Kullak-Ublick GA, Fried M, Mengin-Lecreulx D, Girardin SE. hPepT1 selectively transports muramyl dipeptide but not Nod1-activating muramyl peptides. Can J Physiol Pharmacol 2006;84:1313–9. [37] Dalmasso G, Nguyen HT, Ingersoll SA, Ayyadurai S, Laroui H, Charania MA, et al. The PepT1-NOD2 signaling pathway aggravates induced colitis in mice. Gastroenterology 2011;141:1334–45. [38] Mukhopadhyay S, Varin A, Chen Y, Liu B, Tryggvason K, Gordon S. SR-A/ MARCO-mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens. Blood 2011;117:1319–28. [39] Marina-Garcia N, Franchi L, Kim YG, Hu Y, Smith DE, Boons GJ, et al. Clathrinand dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and NOD2 activation. J Immunol 2009;182:4321–7. [40] Lee J, Tattoli I, Wojtal KA, Vavricka SR, Philpott DJ, Girardin SE. pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling. J Biol Chem 2009;284:23818–29. [41] Charriere GM, Ip WE, Dejardin S, Boyer L, Sokolovska A, Cappillino MP, et al. Identification of Drosophila Yin and PEPT2 as evolutionarily conserved phagosome-associated muramyl dipeptide transporters. J Biol Chem 2010;285:20147–54. [42] Nakamura N, Lill JR, Phung Q, Jiang Z, Bakalarski C, de Maziere A, et al. Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 2014;509:240–4. [43] Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006;444:110–4. [44] Zeissig Y, Petersen BS, Milutinovic S, Bosse E, Mayr G, Peuker K, et al. XIAP variants in male Crohn’s disease. Gut 2014. [45] Tao M, Scacheri PC, Marinis JM, Harhaj EW, Matesic LE, Abbott DW. ITCH K63ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Curr Biol 2009;19:1255–63. [46] Zurek B, Schoultz I, Neerincx A, Napolitano LM, Birkner K, Bennek E, et al. TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation. PLoS ONE 2012;7:e41255. [47] Ver Heul AM, Fowler CA, Ramaswamy S, Piper RC. Ubiquitin regulates caspase recruitment domain-mediated signaling by nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2. J Biol Chem 2013;288: 6890–902. [48] Rosenstiel P, Huse K, Till A, Hampe J, Hellmig S, Sina C, et al. A short isoform of NOD2/CARD15, NOD2-S, is an endogenous inhibitor of NOD2/receptor-interacting protein kinase 2-induced signaling pathways. Proc Natl Acad Sci USA 2006;103:3280–5. [49] Kramer M, Boeck J, Reichenbach D, Kaether C, Schreiber S, Platzer M, et al. NOD2-C2 – a novel NOD2 isoform activating NF-kappaB in a muramyl dipeptide-independent manner. BMC Res Notes 2010;3:224. [50] Lee KH, Biswas A, Liu YJ, Kobayashi KS. Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components. J Biol Chem 2012;287:39800–11. [51] Mohanan V, Grimes CL. Hsp70 binds to and stabilizes Nod2, an innate immune receptor involved in Crohn’s disease. J Biol Chem 2014;289: 18987–98. [52] Yang L, Tang Z, Zhang H, Kou W, Lu Z, Li X, et al. PSMA7 directly interacts with NOD1 and regulates its function. Cell Physiol Biochem 2013;31:952–9. [53] Yeretssian G, Correa RG, Doiron K, Fitzgerald P, Dillon CP, Green DR, et al. Non-apoptotic role of BID in inflammation and innate immunity. Nature 2011;474:96–9. [54] Nachbur U, Vince JE, O’Reilly LA, Strasser A, Silke J. Is BID required for NOD signalling? Nature 2012;488:E4–6. discussion E6-8. [55] Yamamoto-Furusho JK, Barnich N, Xavier R, Hisamatsu T, Podolsky DK. Centaurin beta1 down-regulates nucleotide-binding oligomerization domains 1- and 2-dependent NF-kappaB activation. J Biol Chem 2006;281: 36060–70. [56] Clark NM, Marinis JM, Cobb BA, Abbott DW. MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Curr Biol 2008;18:1402–8. [57] Lecat A, Di Valentin E, Somja J, Jourdan S, Fillet M, Kufer TA, et al. The c-Jun Nterminal kinase (JNK)-binding protein (JNKBP1) acts as a negative regulator of NOD2 protein signaling by inhibiting its oligomerization process. J Biol Chem 2012;287:29213–26. [58] Conde C, Rambout X, Lebrun M, Lecat A, Di Valentin E, Dequiedt F, et al. The inositol phosphatase SHIP-1 inhibits NOD2-induced NF-kappaB activation by disturbing the interaction of XIAP with RIP2. PLoS ONE 2012;7: e41005. [59] Lipinski S, Till A, Sina C, Arlt A, Grasberger H, Schreiber S, et al. DUOX2derived reactive oxygen species are effectors of NOD2-mediated antibacterial responses. J Cell Sci 2009;122:3522–30. [60] Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2007;39:207–11. [61] Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596–604. [62] Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 2010;11:55–62.

[63] Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010;16:90–7. [64] Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology 2010;139. 1630–41, 1641.e1–2. [65] Homer CR, Kabi A, Marina-Garcia N, Sreekumar A, Nesvizhskii AI, Nickerson KP, et al. A dual role for receptor-interacting protein kinase 2 (RIP2) kinase activity in nucleotide-binding oligomerization domain 2 (NOD2)-dependent autophagy. J Biol Chem 2012;287:25565–76. [66] Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S, Martinez J, et al. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol 2013;14:480–8. [67] Sorbara MT, Ellison LK, Ramjeet M, Travassos LH, Jones NL, Girardin SE, et al. The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner. Immunity 2013;39:858–73. [68] Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol 2009;10:1073–80. [69] Vissers M, Remijn T, Oosting M, de Jong DJ, Diavatopoulos DA, Hermans PW, et al. Respiratory syncytial virus infection augments NOD2 signaling in an IFN-beta-dependent manner in human primary cells. Eur J Immunol 2012;42:2727–35. [70] Lupfer C, Thomas PG, Kanneganti TD. NOD2 dependent DC activation is necessary for innate immunity and optimal CD8+ T cell responses to influenza A virus infection. J Virol 2014. [71] Shaw MH, Reimer T, Sanchez-Valdepenas C, Warner N, Kim YG, Fresno M, et al. T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat Immunol 2009;10:1267–74. [72] Caetano BC, Biswas A, Lima Jr DS, Benevides L, Mineo TW, Horta CV, et al. Intrinsic expression of Nod2 in CD4+ T lymphocytes is not necessary for the development of cell-mediated immunity and host resistance to Toxoplasma gondii. Eur J Immunol 2011;41:3627–31. [73] Zanello G, Goethel A, Forster K, Geddes K, Philpott DJ, Croitoru K. Nod2 activates NF-kB in CD4+ T cells but its expression is dispensable for T cellinduced colitis. PLOS ONE 2013;8:e82623. [74] Lin GH, Wortzman ME, Girardin SE, Philpott DJ, Watts TH. T cell intrinsic NOD2 is dispensable for CD8 T cell immunity. PLOS ONE 2013;8:e56014. [75] Conti BJ, Davis BK, Zhang J, O’Connor Jr W, Williams KL, Ting JP. CATERPILLER 16.2 (CLR16.2), a novel NBD/LRR family member that negatively regulates T cell function. J Biol Chem 2005;280:18375–85. [76] Schneider M, Zimmermann AG, Roberts RA, Zhang L, Swanson KV, Wen H, et al. The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-kappaB. Nat Immunol 2012;13:823–31. [77] Shiau CE, Monk KR, Joo W, Talbot WS. An anti-inflammatory NOD-like receptor is required for microglia development. Cell Rep 2013;5:1342–52. [78] Zhang L, Mo J, Swanson KV, Wen H, Petrucelli A, Gregory SM, et al. NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 2014;40:329–41. [79] Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, et al. NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci USA 2010;107:13794–99. [80] Kuenzel S, Till A, Winkler M, Hasler R, Lipinski S, Jung S, et al. The nucleotidebinding oligomerization domain-like receptor NLRC5 is involved in IFNdependent antiviral immune responses. J Immunol 2010;184:1990–2000. [81] Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, et al. NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell 2010;141:483–96. [82] Li L, Xu T, Huang C, Peng Y, Li J. NLRC5 mediates cytokine secretion in RAW264.7 macrophages and modulated by the JAK2/STAT3 pathway. Inflammation 2014;37:835–47. [83] Benko S, Magalhaes JG, Philpott DJ, Girardin SE. NLRC5 limits the activation of inflammatory pathways. J Immunol 2010;185:1681–91. [84] Kumar H, Pandey S, Zou J, Kumagai Y, Takahashi K, Akira S, et al. NLRC5 deficiency does not influence cytokine induction by virus and bacteria infections. J Immunol 2011;186:994–1000. [85] Tong Y, Cui J, Li Q, Zou J, Wang HY, Wang RF. Enhanced TLR-induced NFkappaB signaling and type I interferon responses in NLRC5 deficient mice. Cell Res 2012;22:822–35. [86] Davis BK, Roberts RA, Huang MT, Willingham SB, Conti BJ, Brickey WJ, et al. Cutting edge: NLRC5-dependent activation of the inflammasome. J Immunol 2011;186:1333–7. [87] Neerincx A, Rodriguez GM, Steimle V, Kufer TA. NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. J Immunol 2012;188:4940–50. [88] Yao Y, Wang Y, Chen F, Huang Y, Zhu S, Leng Q, et al. NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens. Cell Res 2012;22:836–47. [89] Meissner TB, Li A, Liu YJ, Gagnon E, Kobayashi KS. The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity. Biochem Biophys Res Commun 2012;418:786–91.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx [90] Meissner TB, Liu YJ, Lee KH, Li A, Biswas A, van Eggermond MC, et al. NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. J Immunol 2012;188:4951–8. [91] Biswas A, Meissner TB, Kawai T, Kobayashi KS. Cutting edge: impaired MHC class I expression in mice deficient for Nlrc5/class I transactivator. J Immunol 2012;189:516–20. [92] Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE, Zimmermann AG, et al. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 2008;451:573–7. [93] Arnoult D, Soares F, Tattoli I, Castanier C, Philpott DJ, Girardin SE. An Nterminal addressing sequence targets NLRX1 to the mitochondrial matrix. J Cell Sci 2009;122:3161–8. [94] Allen IC, Moore CB, Schneider M, Lei Y, Davis BK, Scull MA, et al. NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-kappaB signaling pathways. Immunity 2011;34:854–65. [95] Rebsamen M, Vazquez J, Tardivel A, Guarda G, Curran J, Tschopp J. NLRX1/ NOD5 deficiency does not affect MAVS signalling. Cell Death Differ 2011;18:1387. [96] Soares F, Tattoli I, Wortzman ME, Arnoult D, Philpott DJ, Girardin SE. NLRX1 does not inhibit MAVS-dependent antiviral signalling. Innate Immun 2013;19:438–48. [97] Hong M, Yoon SI, Wilson IA. Structure and functional characterization of the RNA-binding element of the NLRX1 innate immune modulator. Immunity 2012;36:337–47. [98] Xia X, Cui J, Wang HY, Zhu L, Matsueda S, Wang Q, et al. NLRX1 negatively regulates TLR-induced NF-kappaB signaling by targeting TRAF6 and IKK. Immunity 2011;34:843–53. [99] Lei Y, Wen H, Yu Y, Taxman DJ, Zhang L, Widman DG, et al. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 2012;36:933–46. [100] Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 2006;38:240–4. [101] Kovarova M, Hesker PR, Jania L, Nguyen M, Snouwaert JN, Xiang Z, et al. NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J Immunol 2012;189:2006–16. [102] Moayeri M, Sastalla I, Leppla SH. Anthrax and the inflammasome. Microbes Infect 2012;14:392–400. [103] Klimpel KR, Arora N, Leppla SH. Anthrax toxin lethal factor contains a zinc metalloprotease consensus sequence which is required for lethal toxin activity. Mol Microbiol 1994;13:1093–100. [104] Ali SR, Timmer AM, Bilgrami S, Park EJ, Eckmann L, Nizet V, et al. Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage. Immunity 2011;35:34–44. [105] Levinsohn JL, Newman ZL, Hellmich KA, Fattah R, Getz MA, Liu S, et al. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog 2012;8:e1002638. [106] Chavarria-Smith J, Vance RE. Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLoS Pathog 2013;9:e1003452. [107] Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 2007;25:713–24. [108] Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, et al. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci USA 2008;105:7803–8. [109] Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 2007;129:45–56. [110] Gerlic M, Faustin B, Postigo A, Yu EC, Proell M, Gombosuren N, et al. Vaccinia virus F1L protein promotes virulence by inhibiting inflammasome activation. Proc Natl Acad Sci USA 2013;110:7808–13. [111] Liao KC, Mogridge J. Activation of the Nlrp1b inflammasome by reduction of cytosolic ATP. Infect Immun 2013;81:570–9. [112] Gorfu G, Cirelli KM, Melo MB, Mayer-Barber K, Crown D, Koller BH, et al. Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii. MBio 2014;5. e01117–13. [113] Ewald SE, Chavarria-Smith J, Boothroyd JC. NLRP1 is an inflammasome sensor for Toxoplasma gondii. Infect Immun 2014;82:460–8. [114] D’Osualdo A, Weichenberger CX, Wagner RN, Godzik A, Wooley J, Reed JC. CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. PLoS ONE 2011;6:e27396. [115] Finger JN, Lich JD, Dare LC, Cook MN, Brown KK, Duraiswami C, et al. Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J Biol Chem 2012;287:25030–37. [116] Frew BC, Joag VR, Mogridge J. Proteolytic processing of Nlrp1b is required for inflammasome activity. PLoS Pathog 2012;8:e1002659. [117] de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW. Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 2009;29:1251–61. [118] Van Opdenbosch N, Gurung P, Vande Walle L, Fossoul A, Kanneganti TD, Lamkanfi M. Activation of the NLRP1b inflammasome independently of ASCmediated caspase-1 autoproteolysis and speck formation. Nat Commun 2014;5:3209.

15

[119] Sastalla I, Crown D, Masters SL, McKenzie A, Leppla SH, Moayeri M. Transcriptional analysis of the three Nlrp1 paralogs in mice. BMC Genomics 2013;14:188. [120] Im SS, Yousef L, Blaschitz C, Liu JZ, Edwards RA, Young SG, et al. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 2011;13:540–9. [121] Gerlic M, Croker BA, Cengia LH, Moayeri M, Kile BT, Masters SL. NLRP1a expression in Srebp-1a-deficient mice. Cell Metab 2014;19:345–6. [122] Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, et al. NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity 2012;37:1009–23. [123] Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 2002;46:3340–8. [124] Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 2002;71:198–203. [125] Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Nontranscriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 2012;287:36617–22. [126] Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES. Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol 2013;191:3995–9. [127] Ghonime MG, Shamaa OR, Das S, Eldomany RA, Fernandes-Alnemri T, Alnemri ES, et al. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol 2014;192:3881–8. [128] Lin KM, Hu W, Troutman TD, Jennings M, Brewer T, Li X, et al. IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. Proc Natl Acad Sci USA 2014;111:775–80. [129] Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011;469:221–5. [130] Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V. Cutting edge reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol 2011;187:613–7. [131] Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell 2013;49:331–8. [132] Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 2012;13:255–63. [133] Hernandez-Cuellar E, Tsuchiya K, Hara H, Fang R, Sakai S, Kawamura I, et al. Cutting edge: nitric oxide inhibits the NLRP3 inflammasome. J Immunol 2012;189:5113–7. [134] Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, et al. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta. Nat Immunol 2013;14:52–60. [135] Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol 2013;14:1247–55. [136] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. [137] Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440:228–32. [138] Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA 2008;105:9035–40. [139] Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008;9:847–56. [140] Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloidbeta. Nat Immunol 2008;9:857–65. [141] Craven RR, Gao X, Allen IC, Gris D, Bubeck Wardenburg J, McElvania-Tekippe E, et al. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS ONE 2009;4:e7446. [142] Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008;453:1122–6. [143] Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;466:652. [144] Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium. Cell Death Differ 2007;14:1583–9. [145] Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, et al. Glyburide inhibits the cryopyrin/Nalp3 inflammasome. J Cell Biol 2009;187: 61–70. [146] Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 2013;38:1142–53.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 16

F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

[147] Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 2012;492:123–7. [148] Rossol M, Pierer M, Raulien N, Quandt D, Meusch U, Rothe K, et al. Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors. Nat Commun 2012;3:1329. [149] Compan V, Baroja-Mazo A, Lopez-Castejon G, Gomez AI, Martinez CM, Angosto D, et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 2012;37:487–500. [150] Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, et al. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun 2013;4:1611. [151] Triantafilou K, Hughes TR, Triantafilou M, Morgan BP. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J Cell Sci 2013;126:2903–13. [152] Martinon F. Signaling by ROS drives inflammasome activation. Eur J Immunol 2010;40:616–9. [153] Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 2010;11:136–40. [154] Huang H, Hu X, Eno CO, Zhao G, Li C, White C. An interaction between Bcl-xL and the voltage-dependent anion channel (VDAC) promotes mitochondrial Ca2+ uptake. J Biol Chem 2013;288:19870–81. [155] Ichinohe T, Yamazaki T, Koshiba T, Yanagi Y. Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. Proc Natl Acad Sci USA 2013;110:17963–68. [156] Bandyopadhyay S, Lane T, Venugopal R, Parthasarathy PT, Cho Y, Galam L, et al. MicroRNA-133a-1 regulates inflammasome activation through uncoupling protein-2. Biochem Biophys Res Commun 2013;439:407–12. [157] Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 2012;36:401–14. [158] Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 2013;39:311–23. [159] Park S, Juliana C, Hong S, Datta P, Hwang I, Fernandes-Alnemri T, et al. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol 2013;191:4358–66. [160] Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 2013;153:348–61. [161] Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, et al. Microtubuledriven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 2013;14:454–60. [162] Wang Y, Yang C, Mao K, Chen S, Meng G, Sun B. Cellular localization of NLRP3 inflammasome. Protein Cell 2013;4:425–31. [163] Lo YH, Huang YW, Wu YH, Tsai CS, Lin YC, Mo ST, et al. Selective inhibition of the NLRP3 inflammasome by targeting to promyelocytic leukemia protein in mouse and human. Blood 2013;121:3185–94. [164] Dowling JK, Becker CE, Bourke NM, Corr SC, Connolly DJ, Quinn SR, et al. Promyelocytic leukemia protein interacts with the apoptosis-associated speck-like protein to limit inflammasome activation. J Biol Chem 2014;289:6429–37. [165] Bauernfeind F, Rieger A, Schildberg FA, Knolle PA, Schmid-Burgk JL, Hornung V. NLRP3 inflammasome activity is negatively controlled by miR-223. J Immunol 2012;189:4175–81. [166] Haneklaus M, Gerlic M, Kurowska-Stolarska M, Rainey AA, Pich D, McInnes IB, et al. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1beta production. J Immunol 2012;189:3795–9. [167] Razmara M, Srinivasula SM, Wang L, Poyet JL, Geddes BJ, DiStefano PS, et al. CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis. J Biol Chem 2002;277:13952–58. [168] Ito S, Hara Y, Kubota T. CARD8 is a negative regulator for NLRP3 inflammasome, but mutant NLRP3 in cryopyrin-associated periodic syndromes escapes the restriction. Arthritis Res Ther 2014;16:R52. [169] Jin J, Yu Q, Han C, Hu X, Xu S, Wang Q, et al. LRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting Flightless-Imediated caspase-1 inhibition. Nat Commun 2013;4:2075. [170] Labbe K, McIntire CR, Doiron K, Leblanc PM, Saleh M. Cellular inhibitors of apoptosis proteins cIAP1 and cIAP2 are required for efficient caspase-1 activation by the inflammasome. Immunity 2011;35:897–907. [171] Yabal M, Muller N, Adler H, Knies N, Gross CJ, Damgaard RB, et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep 2014;7:1796–808. [172] Mitoma H, Hanabuchi S, Kim T, Bao M, Zhang Z, Sugimoto N, et al. The DHX33 RNA helicase senses cytosolic RNA and activates the NLRP3 inflammasome. Immunity 2013;39:123–35. [173] Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundback P, et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature 2012;488:670–4. [174] Hett EC, Slater LH, Mark KG, Kawate T, Monks BG, Stutz A, et al. Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis. Nat Chem Biol 2013;9:398–405. [175] He Y, Franchi L, Nunez G. The protein kinase PKR is critical for LPS-induced iNOS production but dispensable for inflammasome activation in macrophages. Eur J Immunol 2013;43:1147–52. [176] Grenier JM, Wang L, Manji GA, Huang WJ, Al-Garawi A, Kelly R, et al. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1. FEBS Lett 2002;530:73–8.

[177] Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011;145:745–57. [178] Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM, et al. Control of intestinal homeostasis, colitis, and colitisassociated colorectal cancer by the inflammatory caspases. Immunity 2010;32:367–78. [179] Saleh M, Trinchieri G. Innate immune mechanisms of colitis and colitisassociated colorectal cancer. Nat Rev Immunol 2011;11:9–20. [180] Normand S, Delanoye-Crespin A, Bressenot A, Huot L, Grandjean T, PeyrinBiroulet L, et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc Natl Acad Sci USA 2011;108:9601–6. [181] Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP, Brown EM, et al. NLRP6 inflammasome orchestrates the colonic host–microbial interface by regulating goblet cell mucus secretion. Cell 2014;156:1045–59. [182] Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, Lamkanfi M, et al. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 2012;488:389–93. [183] Kinoshita T, Wang Y, Hasegawa M, Imamura R, Suda T. PYPAF3, a PYRINcontaining APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1beta secretion. J Biol Chem 2005;280:21720–25. [184] Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, et al. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 2012;36:464–76. [185] Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, et al. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet 2006;38:300–2. [186] Messaed C, Akoury E, Djuric U, Zeng J, Saleh M, Gilbert L, et al. NLRP7, a nucleotide oligomerization domain-like receptor protein, is required for normal cytokine secretion and co-localizes with Golgi and the microtubule-organizing center. J Biol Chem 2011;286:43313–23. [187] Wang Y, Hasegawa M, Imamura R, Kinoshita T, Kondo C, Konaka K, et al. PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase1. Int Immunol 2004;16:777–86. [188] Imamura R, Wang Y, Kinoshita T, Suzuki M, Noda T, Sagara J, et al. Antiinflammatory activity of PYNOD and its mechanism in humans and mice. J Immunol 2010;184:5874–84. [189] Lautz K, Damm A, Menning M, Wenger J, Adam AC, Zigrino P, et al. NLRP10 enhances Shigella-induced pro-inflammatory responses. Cell Microbiol 2012;14:1568–83. [190] Eisenbarth SC, Williams A, Colegio OR, Meng H, Strowig T, Rongvaux A, et al. NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature 2012;484:510–3. [191] Joly S, Eisenbarth SC, Olivier AK, Williams A, Kaplan DH, Cassel SL, et al. Cutting edge: Nlrp10 is essential for protective antifungal adaptive immunity against Candida albicans. J Immunol 2012;189:4713–7. [192] Williams KL, Taxman DJ, Linhoff MW, Reed W, Ting JP. Cutting edge: monarch-1: a pyrin/nucleotide-binding domain/leucine-rich repeat protein that controls classical and nonclassical MHC class I genes. J Immunol 2003;170:5354–8. [193] Williams KL, Lich JD, Duncan JA, Reed W, Rallabhandi P, Moore C, et al. The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. J Biol Chem 2005;280:39914–24. [194] Lich JD, Williams KL, Moore CB, Arthur JC, Davis BK, Taxman DJ, et al. Monarch-1 suppresses non-canonical NF-kappaB activation and p52-dependent chemokine expression in monocytes. J Immunol 2007;178: 1256–60. [195] Ye Z, Lich JD, Moore CB, Duncan JA, Williams KL, Ting JP. ATP binding by monarch-1/NLRP12 is critical for its inhibitory function. Mol Cell Biol 2008;28:1841–50. [196] Arthur JC, Lich JD, Aziz RK, Kotb M, Ting JP. Heat shock protein 90 associates with monarch-1 and regulates its ability to promote degradation of NFkappaB-inducing kinase. J Immunol 2007;179:6291–6. [197] Zaki MH, Vogel P, Malireddi RK, Body-Malapel M, Anand PK, Bertin J, et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 2011;20:649–60. [198] Zaki MH, Man SM, Vogel P, Lamkanfi M, Kanneganti TD. Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proc Natl Acad Sci USA 2014;111:385–90. [199] Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, et al. The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 2012;37: 96–107. [200] Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 2011;477:596–600. [201] Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 2006;7: 576–82. [202] Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 2006;7:569–75. [203] Miao EA, Warren SE. Innate immune detection of bacterial virulence factors via the NLRC4 inflammasome. J Clin Immunol 2010;30:502–6.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001

G Model

CGFR-802; No. of Pages 17 F. Barbe´ et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx [204] Kofoed EM, Vance RE. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 2011;477:592–5. [205] Tenthorey JL, Kofoed EM, Daugherty MD, Malik HS, Vance RE. Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Mol Cell 2014;54:17–29. [206] Rayamajhi M, Zak DE, Chavarria-Smith J, Vance RE, Miao EA. Cutting edge: mouse NAIP1 detects the type III secretion system needle protein. J Immunol 2013;191:3986–9. [207] Yang J, Zhao Y, Shi J, Shao F. Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proc Natl Acad Sci USA 2013;110:14408–13. [208] Qu Y, Misaghi S, Izrael-Tomasevic A, Newton K, Gilmour LL, Lamkanfi M, et al. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 2012;490:539–42. [209] Suzuki S, Franchi L, He Y, Munoz-Planillo R, Mimuro H, Suzuki T, et al. Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcdelta. PLoS Pathog 2014;10:e1003926. Franc¸ois Barbe´ obtained a B.Sc. in Agricultural & Environmental Sciences at McGill University in 2013, followed by a graduate certificate in bioinformatics. He recently joined Dr. Maya Saleh’s laboratory within the McGill Complex Traits Group for a M.Sc. in Microbiology & Immunology. His project consists in the characterization of cell death modalities in inflammatory bowel diseases.

17

Todd Douglas completed his B.Sc. Honors in Microbiology and Immunology at McGill University in 2012. He is currently a Ph.D. student under the supervision of Dr. Maya Saleh. His research focus lies in understanding the biochemical mechanisms that regulate the activation of the inflammasome, and their implication in complex inflammatory disorders.

Maya Saleh obtained her Ph.D. in 2001 from the Department of Biochemistry at McGill University studying mechanisms of transcriptional regulation. In 2002, Dr. Saleh joined Merck Research Laboratories and in 2004 moved to the La Jolla Institute for Allergy and Immunology in California where she investigated mechanisms of apoptosis and innate immunity in host defense. Dr. Saleh joined the Faculty of Medicine at McGill University in 2005 and is currently Associate Professor in the Departments of Medicine and Biochemistry and Director of the Inflammation and Cancer Program. She is a McGill University Dawson Scholar, a FRSQ Chercheur-Boursier Senior and a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease. Dr. Saleh’s research group investigates mechanisms of inflammation and immunity, and the role of cell death in host–pathogen interactions and complex diseases with a focus on inflammatory bowel diseases and colon cancer.

Please cite this article in press as: Barbe´ F, et al. Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.07.001