Inflammasome biology in fibrogenesis

Biochimica et Biophysica Acta 1832 (2013) 979–988

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Review

Inflammasome biology in fibrogenesis☆ Xinshou Ouyang, Ayaz Ghani, Wajahat Z. Mehal ⁎ Section of Digestive Diseases, Yale University, New Haven, CT, USA West Haven Veterans Medical Center, New Haven, CT, USA

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Article history: Received 19 December 2012 Received in revised form 20 March 2013 Accepted 23 March 2013 Available online 3 April 2013 Keywords: Fibrosis Inflammasome IL-1b Sterile Inflammation

a b s t r a c t Pathogens and sterile insults both result in an inflammatory response. A significant part of this response is mediated by cytosolic machinery termed as the inflammasome which results in the activation and secretion of the cytokines interleukin-1β (IL-1β) and IL-18. Both of these are known to result in the activation of an acute inflammatory response, resulting in the production of downstream inflammatory cytokines such as tumor necrosis factor (TNF-α), interferon-gamma (IFN-γ), chemotaxis of immune cells, and induction of tissue injury. Surprisingly this very acute inflammatory pathway is also vital for the development of a full fibrogenic response in a number of organs including the lung, liver, and skin. There is evidence for the inflammasome having a direct role on tissue specific matrix producing cells such as the liver stellate cell, and also indirectly through the activation of resident tissue macrophage populations. The inflammasome requires stimulation of two pathways for full activation, and initiating stimuli include Toll-like receptor (TLR) agonists, adenosine triphosphate (ATP), particulates, and oxidative stress. Such a role for an acute inflammatory pathway in fibrosis runs counter to the prevailing association of TGF-β driven anti-inflammatory and pro-fibrotic pathways. This identifies new therapeutic targets which have the potential to simultaneously decrease inflammation, tissue injury and fibrosis. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. Published by Elsevier B.V.

1. Introduction Fibrogenesis is a common widespread pathophysiological response in many tissues after chronic or repetitive injury including infections, autoimmune reactions, and mechanical injury [1–4]. The initial insults can be amplified by an inflammatory response leading to fibrosis, deposition of extracellular matrix, scar formation, and organ failure [3,5–7]. Innate immune cells residing in tissues recognize pathogen invasion with intracellular or surface-expressed pattern recognition receptors (PRRs) by detecting pathogen-associated molecular patterns (PAMPs) [8]. PPRs can also be activated by damage-associated molecular patterns (DAMPs) from injured cells leading to sterile inflammation to distinguish from that induced by pathogens [9]. Inflammasomes are a group of protein complexes that recognize a diverse set of inflammationinducing stimuli that include PAMPs and DAMPs and that control activation of the proteolytic enzyme caspase-1, which in turn regulates maturation of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 [10,11]. Inflammasomes have been found to regulate important aspects of inflammation and tissue repair such as fibrogenesis, a consequence of inflammatory response [12]. Recent studies have

☆ This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. ⁎ Corresponding author at: Section of Digestive Diseases, Yale University, TAC S223A, 1 Gilbert St., New Haven, CT 06520, USA. Tel.: +1 203 785 3411; fax: +1 203 785 7273. E-mail address: [email protected] (W.Z. Mehal). 0925-4439/$ – see front matter. Published by Elsevier B.V. http://dx.doi.org/10.1016/j.bbadis.2013.03.020

characterized distinct molecular activation mechanisms for several sensor proteins and have described the important implication of those components in immune-mediated pathogenesis in humans. We review recent research progress, discuss the different aspects that have been proposed for inflammasome involvement in fibrogenesis during disease development, and highlight the challenges and future directions for this field. 2. Sterile inflammation Inflammation derived by the innate immune response has evolved to efficiently combat infection with pathogenic microorganisms and is critical to host defense. However, such innate mechanisms can also be activated as result of a sterile cell death or injury in the absence of any microorganism, and has been termed ‘sterile inflammation’ [13]. Similar to microbial-induced inflammation, sterile inflammation is characterized by the accumulation of neutrophils and macrophages, and the production of pro-inflammatory cytokines and chemokines, especially tumor necrosis factor (TNF) and interleukin 1-β (IL-1β), as well as reactive oxygen species [13,14]. Sterile inflammation can be induced by many DAMPs including adenosine triphosphate (ATP) and uric acid, which have the ability to activate inflammation in the non-infectious immune response. A large and varied number of DAMPs applied to self molecules have been identified as endogenous factors that can be released or generated into the extracellular environment by dying cells or secondarily abnormal metabolism, and trigger sterile inflammation

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under conditions of cellular stress or injury [15]. The actual repertoire of DAMPs in damaged tissues can vary greatly depending on the type of cell and injured tissue, as illustrated by DAMPs released from parenchymal cells after drug-induced hepatocyte cell death [16]. Prototypical DAMPs derived from necrotic cells include intracellular proteins, such as the chromatin associated protein high-mobility group box 1 (HMGB1) [17], heat shock proteins (HSPs) [18,19], and proteins derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan, heparin sulfate and biglycan. These are generated as a result of proteolysis by enzymes released from dying cells or by proteases activated to promote tissue repair and remodeling [20,21]. Non-protein DAMPs are released or generated during cell death or purine metabolites, such as ATP [22] and uric acid [23]. Recently, mitochondria have emerged as organelles that provide a rich source of DAMPs including mitochondrial DNA, formyl peptides, cytochrome C and ATP. Such a concentration of DAMPs makes mitochondria very potent stimulators of inflammation [24,25]. The variety of DAMP components derived from mitochondria further increases their ability to induce inflammation as they can provide the full range of signals required to initiate sterile inflammation. In addition to those typical DAMP molecules, some biologically active pro-inflammatory cytokines and chemokines, such as IL-1α [26] and IL-33 [27] can be released by necrotic cells, serve a similar function as conventional DAMPs. The importance of cell death in relation to the production of DAMPs and sterile inflammation is that it provides a pathway of regulated pro-inflammatory type of cell death. However, HMGB1 can be secreted by activated macrophages in response to LPS, TNF and TGF-β [28]. This confirms the functional pro-inflammatory actions of HMGB1 independent of cell death. A wide range of in vivo and external particulates have been found to trigger sterile inflammation, in some cases those particulates elicited response associates with prominent fibrogenesis. These particles include inorganic (silica dioxide) [29], organic (cholesterol), crystalline (uric acid crystals), or amorphous such as alum [30,31]. Initially it seems unlikely that significant amounts of organic particulates are present in vivo, however recent examination of liver tissues from humans and mice have shown that with fat-induced inflammation, but not simple steatosis, cholesterol crystals are present inside hepatocytes and come into contact with Kupffer cells [32]. When other non-organic particulates such as talc in intravenous drug users enter organs such as the liver there is also a strong fibrotic response [33]. The further results from our research group have shown that implantation of biomaterials and devices into soft tissues leads to the development of a sterile foreign body response (FBR), which can interfere with implant function and eventually lead to failure [34]. Most of these parts for a number of these particles the inflammatory response results in tissue damage and its attendant fibrogenesis can lead to loss of function. Approximately 20 DAMPs have been identified and it is likely that many others are present in vivo. 3. Components of inflammasomes Until recently, much more was known about how innate immunity is activated by pathogens than by sterile particles and dead cells. The innate immune system possesses multiple families of germ-line encoded PRRs. These PRRs include the Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), and several other receptors [35–37], all of which contribute to immune activation in response to diverse stimuli. These include infectious and noninfectious materials that can cause tissue damage, and endogenous molecules that are released during cellular injury. Activation of these receptors ultimately leads to the production of cytokines that drive the inflammatory response. DAMPs are the best characterized candidates that know to activate PRRs and trigger sterile inflammation. Like all the other innate immune receptor molecules, the NLR proteins are involved in sensing the presence of pathogens via PAMPs; however, they also can detect endogenous danger or stress signals via DAMPs. A subset of NLRs forms a

complex with ASC (apoptosis-associated speck-like protein containing a CARD) to activate caspase-1 and induce maturation and secretion of important pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, whose potent pro-inflammatory activities direct host responses to infection and injury. Those complexes firstly were termed as inflammasome by the Tschopp research group [38]. The diverse functions of inflammasomes in antimicrobial responses, as well as in multifaceted diseases such as acute liver injury and metabolic syndrome, have become evident. Importantly, mutations in components of inflammasome complexes have been associated with a propensity for the development of several immune-mediated diseases in humans. The inflammasome is composed of a sensory molecule that is a member of the family of nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), which can be divided into three subfamilies: NLRP, NOD and ICE-protease-activating factor (IPAF)/neuronal apoptosis inhibitory protein (NAIP) based on their molecular structure and function [10]. These sensory molecules interact with the intermediary adaptor molecule ASC, which in turn can activate cellular proteases. The sensory molecules are cytoplasmic pattern-recognition receptors that recognize a range of molecules ranging from PAMPs to danger signals, such as uric acid and a variety of others. The human NLR family consists of 22 members that can be sub-grouped based on their N-terminal domain which include caspase-recruitment domain (CARD), pyrin domain (PYD), and baculovirus IAP repeat domain (BIR). Upon activation, NLR family members form the multiprotein complexes called the inflammasome. In addition, the cytosolic AIM2 (absent in melanoma 2) molecule is also capable of forming an inflammasome complex. The inflammasome serves as a platform for activation of the cysteine protease caspase-1 which cleaves the pro-forms of the cytokines IL-1β and IL-18 to their active and secreted forms. Caspase-1 may also possess additional functions including regulation of metabolism [39] and unconventional protein secretion [40]. The NLRP3 inflammasome has been associated with a wide range of diseases including infectious, auto-inflammatory, and autoimmune disorders. Bacterial, fungal, viral, and protozoan parasitic pathogens have all been demonstrated to activate the NLRP3 inflammasome [41,42]. NLRP3 is likely responding to the cellular stress induced by the infectious agents and DAMPs and mitochondria are likely central to co-ordinating this process. IL-1β is activated by caspase-1 and is a proximal pro-inflammatory cytokine that broadly affects inflammatory processes. IL-1β is synthesized as a pro-protein without a typical signal sequence that would allow its secretion, and instead its activation and cellular release are controlled by caspase-1 [43]. Caspase-1 is also responsible for the secretion of IL-1α and fibroblast growth factor-2 through an unconventional protein secretion pathway [40]. Caspase-1 is constitutively expressed as pro-caspase-1, but it remains inactive in the cytoplasm until inflammatory effector cells such as monocytes and macrophages receive appropriate stimuli. Known activators are changes in the intracellular ionic environment and bacterial products such as lipopolysaccharide (LPS) and peptidoglycan [44,45]. Inflammasome machinery recruits procaspase-1 either directly through homotypic binding of CARD or indirectly through PYD of ASC protein. 4. Regulation of inflammasome activity In the current model of inflammasome activation there are two distinct signals. The first signal can be triggered by various PAMPs following TLR activation signal as well as IL-1R signaling, and the activation of tumor necrosis factor receptor (TNF-R) (Fig. 1). This priming signal leads to transcription activation of the genes encoding pro-IL-1β, proIL-18 and NLRP3 [46,47]. The second signal is provided by various inflammasome ligands through cytosolic NLR inflammasome activation leading the cleavage of pro-IL-1β and pro-IL-18 into the active forms [48,49]. In the second signal model, after phagocytosis of large crystals such as monosodium urate (MSU), silica, asbestos and aluminum salts,

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Fig. 1. Inflammasome signaling pathways leading to mature IL-1β and IL-18 production: Two major signaling pathways are known to be required in the production of mature IL-1β and IL-18. Signal-1: activation of this pathway results in the production of pro-IL-1β and pro-IL-18 through interaction of various DAMPs/PAMPs and cytokines like TNF-α with TLRs and TNFR. Signal-2: this leads to inflammasome activation through multiple signaling pathways. MSU and other crystals are internalized through phagocytosis that results in the formation of phagolysosome. The phagocytosed crystals cause phagolysosomal membrane damage and release of cathepsin B that triggers inflammasome activation. The other pathway of inflammasome activation is through potassium efflux that takes place when ATP which was released from dying cells binds with the P2X7 receptor. During bacterial infection certain toxins that enter the cells through pore formations are released and may lead to inflammasome activation. The activation of inflammasome results in the generation of serine proteases like caspase-1 from pro-caspase-1. This caspase-1 then cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18 that are secreted out of the cell through secretory vesicles to serve as key mediators for systemic inflammation. Abbreviations: DAMPs, disease associated molecular patterns; PAMPs, pathogen associated molecular patterns; MSU, monosodium urate; ATP, adenosine triphosphate; ROS, reactive oxygen species; TLRs, Toll-like receptors; IL-1β, interleukin-1 beta; IL-18, interleukin-18; TNF-α, tumor necrosis factor-alpha; TNFR, tumor necrosis factor receptor.

lysosomal damage and rupture of lysosomal content might activate NLRP3 (Fig. 2). Notably, one model is the binding of extracellular ATP to P2X7 leading to a potassium efflux from the cell. This efflux leads to the opening of large-pored pannexin-1 channels into the membrane, through which PAMPs and DAMPs can access the cell and directly activate NLRP3 [50]. In addition, the reactive oxygen species (ROS) generated after exposure to PAMPs and DAMPs is proposed to lead to the formation of the NLRP3 inflammasome. It remains unclear, however, how these diverse signals might converge to activate the NLRP3 inflammasome, although a recent publication suggests that ROS is through the ATP dependent potassium efflux and lysosomal rupture, and can activate the inflammasome via the ROS-sensitive ligand, thioredoxin-interacting protein [51]. However signal 1 might be required only for Nlrp3 activation, not other inflammasomes such as NLRC4 and AIM2 [52], since the expression of inflammasome sensors, in particular NLRP3, is relatively low in many cell types and requires a priming signal to be induced [53]. Our unpublished results have

demonstrated that either the first and second signal of inflammasome can be modified by endogenous danger molecule called adenosine, which is usually released from injured cells or generated during ATP metabolism, in which adenosine sustained the amplitude and duration of inflammasome activity through a distinct intracellular signaling pathway. In addition to ATP, cells release other danger signals to activate the inflammasome. For example uric acid crystal particles activates Nlrp3 inflammasome to produce active IL-1β, and macrophages from mice deficient in the inflammasome components of caspase-1, Nlrp3, and ASC, have a highly reduced crystal-induced IL-1β activation capacity [54]. These observations suggest a mechanism whereby immune cell activation can be triggered by solid structures via membrane lipid alteration without the requirement for specific cell-surface receptors [55]. Similarly, our group has reported that acute inflammatory response to biomaterial particulates requires the inflammasome components of Nlrp3, ASC, caspase-1, as well as plasma membrane

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Fig. 2. Inflammasome activation and IL-1β production through Syk pathway: uric acid is released from dying cells during infection and inflammation that crystalizes into MSU crystals. MSU crystals when in access bind to TLR 2/4 receptor and lead to NFκB-mediated pro-IL-1β production. MSU crystals may also bind to cell membrane cholesterol and trigger lipid sorting, which leads to Syk recruitment by ITAM containing receptors enriched in the lipid rafts. At this point two pathways may evolve that lead to mature IL-1β production. i) Syk activation may lead to pro-IL-1β production through CARD9 and NFκB signaling pathway. ii) Syk recruitment turns on PI3K-mediated phagocytosis of MSU crystals. The phagocytosed MSU crystals cause phagolysosomal membrane damage and release of cathepsin B that triggers NLRP3 inflammasome activation. Also phagolysosomal destabilization may result in potassium efflux and generation of ROS to induce inflammasome activation. Activation of inflammasome results in the production of mature IL-1β from pro-IL-1β through caspase-1 that is secreted out of the cell through secretory vesicles to serve as a key mediator for systemic inflammation. Question marks indicate suspected links. Abbreviations: Syk, spleen tyrosine kinase; ITAM, immunoreceptor tyrosine-based activation motif; PI3K, phosphatidylinositol 3-kinase; MSU, monosodium urate; ROS, reactive oxygen species; TLR, Toll-like receptor; IL-1β, interleukin-1β; CARD9, caspase recruitment domain-containing protein 9.

cholesterol, and Syk signaling, demonstrated the participation of the inflammasome in cell–biomaterial interactions and in the development of particulate elucidated inflammatory response [34]. Recent reports reveal a crosstalk between cellular stressassociated processes such as autophagy and inflammasome activity. Autophagy is a cytoprotective process involving the degradation of cellular components through the lysosomal machinery, in which the autophagosome targets those cellular components for degradation in the lysosome, and recycles the constitute molecules [56]. Strikingly, mice lacking Atg16L1, an autophagy component limits production of the inflammatory cytokines IL-1β and IL-18 [57]. This has been suggested to be a result of the impaired clearance of defective mitochondria resulting in elevated levels of ROS, hinting at an involvement of NLRP3 as sensor [58,59]. Given that NLRP3 activation is suppressed by ROS blockade and autophagy negatively regulates ROS generation [59,60], it seems like that autophagic suppression of ROS indirectly inhibits inflammasome activity. Inflammasome activity can also be regulated either through secreted factors or cell–cell interactions, CD4+ effector and memory T cells were demonstrated to suppress NLRP1 and NLRp3 inflammasome-mediated caspase-1 activity and IL-1β secretion [61]. Examples of cytokines that

mediated negative regulation of inflammasome activity is provided; type I interferon (IFN-I) was also found to inhibit IL-1β secretion as well as inflammasome activation [62]. The inhibition is dependent on the interactions between T cells and macrophages or dendritic cells respectively, leading transcriptional and post-transcriptional down regulation of inflammasome activity [61,62]. 5. Activation of the inflammasome in different cell populations It has been long assumed that immune cells of myeloid origin, including monocytes, macrophages, neutrophils, and dendritic cells are the only sources of IL-1β as well as the localization of inflammasome components [63]. However, there is an increasing evidence that inflammasomes exist and are functionally active in several tissues, including lung, liver, kidney and skin, and a variety cell types express inflammasome components including T cells, myofibroblasts/fibroblasts [64], keratinocytes, epithelial cells, hepatocytes, and hepatic stellate cells [65–70,70–73,66]. The recent evidence has shown that both Nlrp1 and Nlrp3 expression is present in myeloid and non-myeloid cells, highest levels of Nlrp1 and Nlrp3 exist in peripheral blood leukocytes, T cells, and Langerhans cells. Nlrp1 is present in glandular epithelial structures

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such as lung and gut. In contrast to Nlrp1, Nlrp3 shows a more restricted tissue distribution with expression mainly in non-keratinizing epithelia in the oropharynx, esophagus, and ectocervix [67]. In the liver NLRP1, 2, 3, 6, 10, 12, and NLRC4 are expressed at the mRNA level [67]. Kupffer cells, the liver resident macrophages, can produce significant amounts of IL-1β [74] and express most of the NLRs [75]. 5.1. Acute activation verses chronic activation The role of inflammasome components was identified in the acute inflammatory response of macrophages to uric acid crystals [12]. This has been followed by a demonstration of a role for inflammasome components in a surprisingly wide range of biological processes some of which like gout are acute, but others such as fibrosis occur over months and years [76]. The proposed activation paradigm of signal 1 (TLR-mediated transcriptional up-regulation) and signal 2 (assembly of inflammasome components and cleavage of caspase-1) works well for acute inflammatory responses. However for chronic inflammation there is a defect in the proposed scheme. The defect is that signal 1 has an acute time course. At the mRNA level there is a peak in pro-IL-1β at 3–5 h, and at the protein level at 16–18 h. This is followed by a rapid decline by 24 h. This acute response cannot be converted into a sustained response by simply providing a sustained signal with a TLR agonist. This has been recognized in many forms and is best characterized for the TLR4 ligand LPS, and labeled LPS tolerance [77]. This is a complex and broad phenomenon with alterations in the TLR signaling pathway in multiple places [77]. The breadth of LPS tolerance is demonstrated by the fact that there is a loss of response to other TLR ligands as well, described as heterotolerance. Sustained exposure to stimuli providing signal 2 also does not result in sustained activation, but rather cell death. This occurs with signals such as ATP and also particulates such as uric acid crystals. This highlights that we do not yet understand which stimuli result in sustained inflammasome activity. The identity of these signals is speculative but they would have to be maintained for extended periods and be pro-fibrogenic. There are likely many other inputs into each type of cell which can influence inflammasome activity and a prime candidate for sustained activation of the inflammasome is adenosine which is elevated in tissues during injury and inflammation and has a well documented pro-fibrotic role. The kinetics of macrophage activation in liver fibrosis has at least two phases. During the development of fibrosis liver macrophages contribute to the deposition of a matrix, and during the recovery phase they contribute to matrix degradation [78]. The reduced fibrosis in mice lacking inflammasome components suggests that the inflammasome is important in at least the initial phase of macrophage dependent deposition of fibrosis. It will require a generation of timed and inflammasome selective depletion of inflammasome components to address the role of inflammasome components during the resolution of fibrosis. Immune cells other than tissue macrophages are known to have an important role in liver fibrosis. These include natural killer (NK) and NK-T cells, T cells with Th1, Th2, Th17 and Th22 skewing as well as dendritic cells [79]. The role of inflammasome components in many of these cell populations is just beginning to be identified. The best characterized is inflammasome-mediated dendritic cell activation particularly in response to particulate adjuvants such as alum. The role of dendritic cells in different stages of NASH-induced inflammation and fibrosis was recently clarified when it was shown that ablation of DC resulted in greater fibro-inflammation [79]. Dendritic cells are known to develop an activated phenotype in fibrotic liver diseases, but it remains to be tested if this is dependent on inflammasome components [80]. 6. Inflammasome components in organ models of fibrosis The common experimental tools available to investigate the role of inflammasome components in organ specific fibrosis are mice

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with deficiencies in various inflammasome molecules, use of receptor agonists and antagonists, and detection of release of DAMPs. The first two of these approaches do not distinguish between the contribution of PAMPs and DAMPs to liver injury, and the third provides indirect evidence that a DAMP may be responsible. More convincing evidence comes from the demonstration that removal of a particular DAMP results in less liver pathology, and this has been done for HMGB1 in IR and APAP toxicities [17,81]. A number of these approaches have been tried in lung, liver, skin and kidney fibrosis but they have not all been applied in all of these. 7. Lung fibrosis Pulmonary fibrosis occurs in response to a number of insults including exposure to toxins in cigarette smoke, and hypersensitivity to allergens in bacterial, fungal and animal products. In addition particulates such as silica and asbestos induce inflammation and fibrosis and it also occurs secondary to connective tissue diseases such as scleroderma and certain drugs such as bleomycin. The lungs were one of the first organs in which a role for inflammasome components was demonstrated using a bleomycin injury model [82]. Mice lacking the IL-1R and the adaptor ASC had significantly less neutrophilic and lymphocytic infiltrates. Bone marrow chimeras constructed using MyD88 deficient cells and mice gave a very clear result, with the development of inflammation when KO bone marrow was injected into WT mice, but not when wild-type bone marrow was injected into KO mice. Critically there was also reduced matrix remodeling and ultimately less fibrosis at day 11 after bleomycin nasal installation. Very direct evidence for a role of IL-1R in lung inflammation and fibrosis was provided by direct installation of IL-1β into the lungs. After 7 days there was inflammation and matrix deposition. The in vivo role of IL-1β was demonstrated by using the IL-1R antagonist given at the same time as bleomycin. This work has been extended to identify uric acid as one of the proximal signals for inflammasome activation in bleomycin lung injury [12]. The reduction of uric acid synthesis by using an inhibitor of uric acid synthesis or uricase to increase uric acid breakdown resulted in reduced lung inflammation, repair and fibrosis. The addition of uric acid recapitulated in lung inflammation in an NLRP3 and IL1-R dependent manner. This seems very surprising because there is a requirement for uric acid crystals in the lung, not just soluble uric acid for activation of the inflammasome. The induction of lung injury by a single intra-nasal dose of pancreatic elastase results in the destruction of the matrix and an acute inflammatory response, presumably by the release of DAMPs. In this model, which has features of chronic obstructive pulmonary disease, the development of emphysema was dependent on NLRP3 and IL-1R1, and importantly could be inhibited by a clinically available IL-1R antagonist [83]. Exogenous particulates are also known to induce inflammasome activation. In some professions such as mining, workers repeatedly inhale particles of silica which can result in a chronic interstitial pulmonary disease with progressive fibrosis [84]. Inhalation of asbestos results in similar chronic lung fibrosis [84]. A role for pulmonary macrophages was suspected to have a major role in the lung fibrosis because macrophages from patients were shown to produce high levels of IL-1β and in vitro exposure of macrophages to silica crystals results in the production of IL-1β [85]. It has been shown that the in vitro production of IL-1β by macrophages and the in vivo production of fibrosis were dependent on NLRP3 and caspase-1 [86]. 8. Liver fibrosis In common with other organs repeated and chronic injury results in a severe fibrotic response in a significant proportion of people. This is seen with chronic viral infections, and non-infectious etiologies. The non-infectious etiologies are of particular interest as in the developed

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world they are rapidly becoming the major reason for liver disease. Alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), ischemia–reperfusion (IR) and drug-induced liver injury are the major non-infectious liver diseases. Alcoholic liver disease encompasses a spectrum of pathologies which range from mild steatosis to a fulminant hepatitis, to the silent development of fibrosis. The factors which result in certain people to develop these pathologies is not well understood, but it is clear that there is a role for inflammation and fibrosis in the ultimate organ dysfunction. A role for TLRs specifically TLR4 was demonstrated by using receptor deficient mice [87]. With respect to the ability of PAMPs and DAMPs to activate TLRs, the ability of reduction in the bacterial load of the intestine to improve liver damage pointed to a major role for PAMPs [88]. A single study has extensively examined the role of many inflammasome components in a mouse model of alcoholic liver disease [89]. In mice lacking ASC, caspase-1 or IL-1R there is significantly less steatosis, inflammation and liver injury. This was associated with a reduction in a number of inflammatory cytokines. Alcohol-induced liver injury results in a relatively mild fibrosis, but this was significantly reduced in caspase-1 deficient mice. The use of bone marrow chimeras revealed that the requirement of inflammasome components was on bone marrow derived, rather than parenchymal cells. This is consistent with studies in obesityinduced insulin resistance and NASH where the requirement for TLR2, TL4 and JNK1 in the development of inflammation and insulin resistance is on bone marrow-derived cells [90–92]. There was a reduction in the fibrotic area in liver histology, a reduction in gene expression for TGF-β1 and pro-Col1α1, and serum levels of PIIINP, TIMP-1 and hyaluronic acid. Also daily administration of IL-1R antagonist was able to reduce the development of alcohol-induced hepatitis, to reduce the progression of injury, and to accelerate the rate of improvement after stopping alcohol. The effect of IL-1R antagonist on fibrosis was not assessed, but it is likely that if given before initiation of injury it would minimize the development of fibrosis. Its effects on established fibrosis are less predictable. Non-alcoholic steatohepatitis (NASH) has many of the histological and biochemical features of ASH, but does not have the flares of acute life-threatening hepatitis and liver failure [93]. With the obesity epidemic in developing countries the prevalence of NASH and its precursor non-alcoholic fatty liver disease (NAFLD) is increasing. Although the clinical course is usually asymptomatic, similar to ASH there is a clear progression to fibrosis and cirrhosis in a significant minority of patients. Some of the difficulties with NASH have been the low level of liver injury in animal models, and the subsequent difficulty in demonstrating elevations in DAMPs. Analogous to ASH elevations in the TLR4 ligands LPS have been demonstrated in rodent models, and in human NASH due to intestinal bypass [94]. There is a controversy as to the role of free fatty acids in activating Toll receptors, but there are some reports of FFA activating TLR4 [95]. In the absence of TLR4 and TLR9 many aspects of NASH including histological score, hepatocyte apoptosis, ALT and fibrogenic markers are reduced [74,96,97]. TLR9 is required for normal amounts of IL-1β production from Kupffer cells in NASH, which induces hepatocyte death and HSC activation. IL-1β also induces lipid metabolism and hepatocyte steatosis. These studies also provided insight into an open question regarding IL-1β in inducing tissue injury. It relates to the fact that the IL-1 receptor does not have a death domain, and it was unclear how it can induce hepatocyte death. It was recently demonstrated that although IL-1β cannot induce cell death by itself, it sensitizes hepatocytes to signal from conventional cell death signals such as TNF-α. [74,98]. Ischemia–perfusion (IR) injury is not associated with fibrosis but is an important clinical condition, and also an experimental model to understand how the liver responds to injury [99]. IR injury encompasses at least two different stages of insults, with an initial injury during cold preservation during which sinusoidal cells are predominantly damaged [100]. This is followed by a period of warm IR

which is associated with ischemic damage, and upon reperfusion an inflammatory response which is driven mostly by the innate immune system [101]. As for most models the role of TLR4 was initially tested on IR injury and analogous to the data of inflammasomes in alcoholic liver injury there was a requirement for TLR4 on non-parenchymal cells [102]. In contrast to alcohol-induced liver injury there is a direct evidence for DAMPs driving IR injury because there is an elevation in the DAMP HMGB1, and its inhibition results in a reduction in IR injury. In vivo evidence for a requirement of the NLRP3 inflammasome comes from experiments in which there was silencing of the NLRP3 gene. NLRP3 specific plasmids reduced ALT in a dose dependent manner as compared to control, and also reduced IL-1β and improved liver histology and hepatocyte apoptosis [103]. A role for the IL-1β pathway is also suggested by the rise in serum IL-1β, peaking at 8 h after reperfusion. In a different study there was a lack of a difference in liver injury between wild-type and IL-1R deficient mice which suggests that a role for IL-1β in causing liver injury is either minimal, redundant or limited to certain time points after reperfusion [104]. 9. Dermal fibrosis Systemic sclerosis is a form of scleroderma with deposition of collagen in many organs including the skin. This results in a scarred and hard skin surface with redness and pruiritis. The condition is associated with myofibroblast activation and increased deposition of collagen. A study examining the up-regulation of gene transcripts in three systemic sclerosis cell lines with normal dermal fibroblasts identified genes among the inflammasome components as being up-regulated [64]. A functional readout of inflammasome activity was increased secretion of IL-1β and IL-18 by the systemic sclerosis fibroblasts. A causal association between caspase-1 and fibrogenesis was made by using a caspase-1 inhibitor in vitro which resulted in a decrease in the production of collagen 3A1 protein, and a decrease in α-smooth muscle actin. This was a specific phenomenon as f-actin remained unchanged. In vivo experiments using a model of bleomycin-induced dermal fibrosis showed that in NLRP3 and ASC deficient mice there was almost no increase in skin thickness due to collagen deposition, in contrast to an almost doubling of skin thickness in wild-type controls. This was correlated by a reduction in hydroxproline secretion by dermal fibroblasts form these mice. Interestingly this study provided data on the lungs as well, and there was fibrosis in the wild-type but not in the knockout mice. This study leaves open questions about the nature of the initiating DAMP, the origins of the sensing cell and the relative roles of IL-1β and IL-18. 10. Direct and indirect fibrotic responses of inflammasome activation An important question is whether the pro-fibrogenic effects of inflammasome activation are due to direct activation of matrix producing cells such as myofibroblasts by DAMPs, or if the effects are due to DAMP-induced activation of immune cells such as macrophages with IL-1β and IL-18-mediated activation of myofibroblasts (Fig. 3). There is a good experimental evidence to support both pathways. In support of the direct pathway hepatic stellate cells (HSC) and dermal fibroblasts both express inflammasome components [64,66]. Stimuli such as uric acid crystals, which are known to activate the NLRP3 inflammasome pathway, induce an activation phenotype in HSC cell lines and primary mouse HSC. Uric acid crystal changes include up-regulation of TGF-β, collagen1, the development of a more stellate shape, and the loss of chemotaxis [66]. These changes did not occur if the HSC were lacking the inflammasome component ASC. As stated above dermal fibroblasts can produce IL-1β, and this can be inhibited by a caspase-1 inhibitor. Due to the fact that the IL-1R signals via a MyD88 domain, in common with most Toll receptors, and results in the up-regulation of pro-IL-1β, the release of IL-1β can initiate a positive feedback cycle with IL-1β contributing to its own production.

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Fig. 3. Direct and indirect pathways of HSC activation: Hepatocyte injury and death induced by various hepatotoxic insults like ethanol, APAP, IR, drugs, toxins and viruses result in the release of DAMPs/PAMPs along with the enhanced translocation of microbial products across the gut epithelium. These DAMPs/PAMPs may induce activation of hepatic stellate cells in two ways. (1) Direct activation: HSCs are activated directly through the interaction of DAMPs/PAMPs with the TLRs located on the HSCs as well as by various growth factors like TGF-β and PDGF released from damaged hepatocytes. (2) Indirect activation: during this pathway, activation of Kupffer cells by DAMPs/PAMPs results in the production and release of various cytokines like IL-1β and TNF-α. These cytokines then bind with the receptors located on the HSCs and result in their activation that lead to hepatic fibrosis. Abbreviations: APAP, N-acetyl-p-aminophenol (acetaminophen); IR, ischemia–reperfusion; DAMPs, disease associated molecular patterns; PAMPs, pathogen associated molecular patterns; HSC, hepatic stellate cell; TLRs, Toll-like receptors; IL-1β,, interleukin-1β; TNF-α, tumor necrosis factor-alpha; LPS, lipopolysaccharide.

There is also significant data to support an indirect pathway. Peritoneal and tissue macrophages such as Kupffer cells are the best characterized cells that respond to inflammasome activating signals with the production of IL-1β and IL-18. The question has been if these cytokines have a role in fibrogenesis. Based on the properties of TGF-β, which is very fibrogenic but also immunosuppressive it seemed unlikely that very pro-inflammatory cytokines such as IL-1β can also have pro-fibrogenic properties. During experimental liver fibrosis IL-1 levels are elevated, and there is significantly less liver fibrosis in IL-1R deficient mice [105]. In an alveolar basal epithelial cell line IL-1β was shown to stimulate transcription of TGF-β via an NF-κB and AP-1 pathway [106]. Similar results were obtained from primary mouse hepatic stellate cells with the up-regulation of collagen α1 and the down regulation of Bambi [74]. In vivo direct installation of TGF-β into the lungs resulted in an inflammation and fibrogenesis [82]. In addition cells which are not typically thought of as fibrogenic can undergo a fibrogenic transformation in response to IL-β, and this was shown to occur for dermal microvascular endothelial cells, which

underwent a transformation to myofibroblasts with functional collagen synthesis [107]. 11. Future developments These current inflammasome activation pathways should be seen as the minimum activation requirements with the identification of regulatory pathways as high priority. Such regulatory pathways may account for the differences in scale and type of response in different mouse strains and individuals, and are candidates for therapeutic intervention. Among the regulatory points of interest are the recently identified G protein coupled receptors (GPCRs) which have metabolites such as lactate and beta-hydroxybutyrate as ligands [108]. The initiation of immune responses in many cells results in a major metabolic shift with a decrease in the tricarboxylic cycle and an increase in glycolysis resulting in the production of molecules such as lactate and ketone bodies which are ligands for GPCRs and may regulate inflammasome biology [109]. Further areas are the identification of

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specific DAMPs which are important in different types of liver injury and the testing of DAMP and inflammasome specific therapeutic agents. A diverse range of drugs and molecules including glyburide, colchicines and anakinra are already under investigation as inhibiting aspects of inflammasome activation [89,110,111]. Some current drugs such as methotrexate are known to induce chronic liver injury. Elevation of tissue adenosine levels is thought to be an important mechanism of the action of methotrexate and it will be interesting to test if adenosine interacts with the inflammasome pathway. In summary a requirement for inflammasome components has been demonstrated in a wide range of fibrotic responses ranging from the liver, lung and skin. The production of IL-1β and activation of the IL-1R appears to be a key consequence of inflammasome activation relevant to fibrosis. 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