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Interplay between microRNAs and host pathogen recognition receptors (PRRs) signaling pathways in response to viral infection
Virus Research 184 (2014) 1–6
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Virus Research journal homepage: www.elsevier.com/locate/virusres
Review
Interplay between microRNAs and host pathogen recognition receptors (PRRs) signaling pathways in response to viral infection Ao Zhou a , Shuaifeng Li a , Junjing Wu b , Faheem Ahmed Khan a , Shujun Zhang a,∗ a Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China b Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Institute of Animal Husbandry and Veterinary, Hubei Provincial Academy of Agricultural Sciences, Wuhan 430064, China
a r t i c l e
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Article history: Received 20 October 2013 Received in revised form 17 January 2014 Accepted 17 January 2014 Keywords: PRRs PAMP MicroRNAs Innate immune response
a b s t r a c t Antimicrobial response is greatly influenced by microRNAs (miRNAs) which are the important posttranscriptional regulators of gene expression. Simultaneously, host pathogen recognition receptors (PRRs) engaged by pathogen-associated molecular patterns (PAMPs) also play critical roles in activating innate immunity against microbial infection. Emerging evidences suggest that the interaction between microbial-regulated miRNAs and important PRRs signaling pathways influence host immune response to microbial pathogens. In this manuscript, we describe the roles of miRNAs in virus-regulated innate immune pathways and the crosstalk between miRNAs and PRRs, further breaking out the mechanistic dissection of miRNAs–PRRs in viral infection and the development of the prognosis of disease and novel miRNA-therapeutic strategies targeting immunity. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miRNAs and Toll-like receptors signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miRNAs and cytoplasmic RIG-I-like receptors (RLRs) signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miRNAs participate in NOD-like receptors (NLRs)-mediated innate immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Host pathogen recognition receptors (PRRs) which including Toll-like receptors (TLRs), RIG-I-like receptors (RIGs), Nod-like receptors (NLRs) and C-type lectin receptors (CLRs) are essential for the survival of the microorganism and are also critical in triggering innate immune defenses through binding to pathogenassociated molecular patterns (PAMPs), which leads to activation of intracellular signaling pathways and distinct anti-pathogen responses (Meylan et al., 7098; Rämet et al., 2011). Once PRRs signaling pathways are activated, host can trigger the production of pro-inflammatory cytokines and type 1 interferon (IFN) to inhibit viral replication (Takaoka et al., 2005; Yun et al., 2011). PRRs are expressed in macrophages, Dendritic cells (DCs), and
∗ Corresponding author. Tel.: +86 027 87281813; fax: +86 027 87281813. E-mail address: [email protected] (S. Zhang). 0168-1702/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.virusres.2014.01.019
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various nonprofessional immune cells. In addition, each member of PRRs reacts with specific PAMPs to trigger the corresponding downstream signaling events and eventually induce inflammation, innate immunity, even adaptive immune response (Takeuchi and Akira, 2010).miRNAs are highly conserved, endogenous noncoding RNA molecules, which regulate post-transcriptional gene expression to prevent protein accumulation. It has been shown that miRNAs regulate a wide range of critical physiologic and pathological processes, including cellular proliferation and differentiation, apoptosis and inflammation by inducing mRNAs degradation or translational repression of target genes (Zhao and Srivastava, 2007; Bartel, 2009). In rare cases, miRNA can also act as positive regulator when bound together with other 3 UTR binding complex (Vasudevan et al., 2007), for instance, miR-214 regulates the expression of lactoferrin that mediated pro-apoptotic activities in mammary epithelial cells (Liao et al., 2010). Adrian et al. (2012) summarized that MiR-29 family play an important role in adaptive immune system for setting the threshold in infection-associated
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thymic involution, helper T cell differentiation and lymphocyte oncogenesis (Adrian et al., 2012). In addition to participating in physiologic and pathological processes, an increasing number of studies suggest that miRNAs play pivotal roles in the regulation of viral infections (Sullivan and Ganem, 2005). The data demonstrates that miRNAs can not only control host gene expression and affect immune cell development and function, but also regulates the viral life cycle to directly interfere viral replication. MiR-323, miR-491 and miR-654 inhibit H1N1 influenza A virus replication via targeting the PB1 gene (Li et al., 2010), whereas miR-196 and miR-296 regulate type 1 interferon-associated pathways to attenuate viral replication in liver cells (Pedersen et al., 2007). Tuddenham and Pfeffer (2011) had also summarized that at least 14 mature miRNAs encoded by cytomegalovirus and their targets in viral and host cells (Tuddenham and Pfeffer, 2011). MiR-7, miR-187, miR200c, or miR-1275 were first shown to be involved in infection with two influenza A virus strains, A/Udorn/72 and A/WSN/33 or cellular antiviral responses (Buggele et al., 2012). Although increasing evidence shows that miRNAs are involved in host innate immune responses to regulate virus infection (Lu and Liston, 2009; Bi et al., 2009), the exact mechanisms to explain the role of miRNAs in host immune response to viral infection still needs to be unveiled. In addition, the nature of correlation between miRNAs, PRRs signaling pathways and innate antiviral immune is just beginning to be explored and needs future investigation. In this review, we will summarize and explore the roles of miRNAs in the regulation of the innate immune response. We will also discuss the crosstalk between miRNAs and PRRs signaling pathways in response to viral infection.
2. miRNAs and Toll-like receptors signaling pathway As key PRRs, Toll-like receptors have important roles in host innate immune responses against microbial pathogen infections via mediating activation of the transcription factor NF-B or regulating expression of type 1 interferon (Takeuchi et al., 2002; Akira et al., 2006). In turn, TLR-activates downstream signals which can modulate TLR signal transduction by interacting with upstream signaling to maintain immunological balance (Brint et al., 2004; Liew et al., 2005). TLR signaling pathways are divergent in two parts: MyD88dependent and MyD88-independent pathways. Although there is some data that portrays the interaction between TLRs signaling pathways and miRNAs that regulates virus replication and some virus also utilize the relationship between them to evade host immune responses, the exact mechanisms are not largely known. The insights gained in relative studies support the idea that miRNAs act as a key regulator of gene expression to involve in TLRmediated innate immune response (O’Neill et al., 2011). Taganov et al. (2006) had found that miR-146, miR-132 and miR-155 were significantly up-regulated in response to lipopolysaccharide (LPS) as TLR4 modulator, indicating that miRNAs have an important role in mammalian response to micro-organisms infection (Taganov et al., 2006). The data given by Liu et al. (2009) suggested that miR-147 could significantly attenuated LPS stimulated TNF-␣ and IL-6 production of TLR induced inflammatory responses, whereas its knockdown enhanced LPS and poly (I:C) induced TNF␣ and IL-6 expression, indicating that miR-147 represses TLR4 and TLR3 induced inflammatory responses. In addition, miRNAs also can target TLR4 or key TLR signaling proteins to regulate TLR-mediated innate immune in response to pathogen infection. MiR-223 was predicted as an important candidate to regulate TLR3 and TLR4 expression (Chen et al., 5654). Moreover, the finding had revealed that let-7i regulated TLR4 expression through translational repression and triggered epithelial innate immune against Cryptosporidium parvum infection (Chen et al., 2007), Whereas
TLR2 is a potential target for miR-105 through in silico analysis and the interaction between miR-105 and TLR2 can result in the down-regulation of cytokine production and suppress excessive inflammation (Benakanakere et al., 2009). There are also other evidences suggesting that miR-21 was a negative regulator for TLR4 signaling to activate NF-B and decrease IL-10 production by targeting a pro-inflammatory protein PDCD4 (Sheedy et al., 2010). MiR-146/152 could regulate TLR-triggered innate immune response and Ag-presenting capacity of DCs by targeting CaMKII␣ that enabled upgrade TLR-induced production of pro-inflammatory cytokines (Liu et al., 2010). Especially, viral-encoded miRNA have been shown to autoregulate viral mRNA or deregulate cellular mRNAs, but the function of the major viral miRNAs still remains to be determined. Insight into the pathogenic nature of these viruses’ miRNAs in innate immunity will provide new therapeutic strategies against virus infection. For example, a date from Abend et al. suggests that KSHV-encoded miRNAs (miR-K5 and miR-K9) expression results in down regulation of MyD88 and IRAK1, which are vital molecules in TLR/IL-1R signaling cascade, leading to the change in virus infection (Abend et al., 2012). Accumulated information has also revealed that TLRs can induce the expression of miRNAs, which in turn regulate virus infection through targeting miRNAs-interacted genes or protein. O’Neill et al. had summarized that the expression of miRNAs was modulated by TLR signaling (O’Neill et al., 2011). Moreover, there had been more evidences that TLR-inducted miRNAs, in turn, negatively regulated TLR signaling. Upon stimulation of multiple TLRs, miR-147 can regulate murine macrophage inflammatory responses (Liu et al., 2009). Through studying the mechanisms underlying the role of TLR-3 activation on HIV replication, a group of scientists has found that activated TLR-3 highlighted the expression of cellular miRNAs to inhibit HIV replication (Zhou et al., 2010). The expression of microRNA-29b, -29c, -148b, and -152 were up-regulated under TLR3 activation by poly I:C in tumor-derived cell lines and primary tumors (Galli et al., 2013), indicating that relational miRNAs may have anti-viral function. In addition, miR-155 has been identified as an anti-HIV-1 factor that results in inhibiting HIV-1 replication (Swaminathan et al., 2012). Although some findings were existed to support that miRNAs is pivotal in antiviral immune response by a variety of strategies, this function triggered by TLR signaling pathway still remains unclear. It has also been shown that negative regulation of TLR signaling is essential for limiting inflammation and benefiting viral replication (Stack et al., 2005). Thus, we speculate that when TLR signaling inhibitors are targeted by miRNAs, TLRs induce inflammatory cells to recognize invading microbial pathogens and activate innate immune responses to block viral infection, although there is presently little experimental evidence to support that hypothesis. Through bioinformatic analyses and experimental approaches, it has been known that a number of genes can be targeted by miRNAs (Lewis et al., 2005), and it is also possible that negative regulators of TLRs such as RP105, ST2L and IRAK-M (Antosz ´ and Choroszynska, 2013) can be targeted by miRNAs which intern enhances TLR signaling triggered immune responses.
3. miRNAs and cytoplasmic RIG-I-like receptors (RLRs) signaling pathway RIG-I-like receptors (RLRs) has three DExD/H box helicases, including retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated antigen 5 (MDA5) and laboratory of genetics and physiolpgy2 (LGP2) that positively regulate the RIGI/MDA5 mediated antiviral responses and can potentiate INF production during viral infection. But its precise role in regulating
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RLRs signal remains to be determined (Yoneyama et al., 2004; Yoneyama and Fujita, 2009). RLRs are key regulatory factors to induce type 1 interferon (IFN) mediated innate immunity to suppress viral replication (Yoneyama and Fujita, 2007; Fujita et al., 2007; Nasirudeen et al., 2011). In addition, it has become increasingly evident that virus also can regulate RLR-mediated innate immune by miRNAs and the role of miRNAs in regulating RLR signaling pathway are to be identified and understood. Recently, a report states that miR-146a was a negative regulator of RIG-I antiviral pathway. miR-146a can impair RIG-I signaling and down-regulate RIG-I-triggered type 1 IFN production to promote VSV replication in macrophages by targeting TRAF6, IRAK1 and IRAK2, which were associated with important regulators in RIG-I signaling pathway (Hou et al., 2009). miRNA-155 was able to target IKK and FADD, which were important protein in RLR signaling pathway, and over-expression of miR-155 down-regulated these target protein via mRNA degradation or translation repression (Xiao et al., 2009). In addition, it has been identified that virusencoded miRNAs are expressed and involved in virus infection to influence RIG-I antiviral pathway and host immune response. The results presented by Silva and Jones (2012) suggested that bICP0 protein expression and productive infection were interfered by BHV-1 miRNAs, which expressed during latency and stimulated the RIG-1 signaling pathway that correlated with activated type I IFN signaling, although they have no valid evidence to depict the mechanism how the LR-encoded miRNAs were recognized by RIG-I (Silva and Jones, 2012). Apart from miRNA-activated RIGI signaling, RIG- I signaling also regulates miRNA abundance in response to infection with virus. miR-155 as an important immune regulator was induced in macrophages through RIG-I/JNK/NF-kBdependent pathway, resulting in promoting type I IFN signaling and suppressing viral replication (Wang et al., 2010). Strikingly, another key player in innate immunity, miR-146 was up-regulated during virus infection in macrophages through RIG-I-NF-kB-dependent and TLR-MyD88-independent pathways, but inducible miR-146
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negatively inhibits RIG-I-dependent type I IFN signaling production, leading to increase virus replication (Hou et al., 2009). New data had been emerged that RIG-I mediated signaling was able to up-regulate 37miRNAs expression and RIG-I-inducible miR-23b significantly suppressed the entry of rhinovirus 1B (RV1B) though targeting VLDLR as RV1B receptor, but not post-entry viral replication (Ouda et al., 2011). Bioinformatic analysis of the 3 untranslated regions (UTRs) of genes involved in RLR signaling pathway using the prediction program TargetScan (http://www.targetscan.org/) and miRNAda (Grimson et al., 2007) indicated that many miRNAs can regulate RLR signaling pathway by targeting key signaling proteins or negative regulators for RLR signaling (Fig. 1). However, when virus infection, the role of miRNAs involved in RLR signaling pathway regulating immune response still needs to be confirmed via experimental evidence. 4. miRNAs participate in NOD-like receptors (NLRs)-mediated innate immune response It has been demonstrated that Cytoplasmic NLRs are important regulators of innate and adaptive immune responses in microbial pathogenesis and mammalian immunity (Miao et al., 2010; Williams et al., 2010). NLRs proteins, innate immune sensors against microbial infection, combining with some signaling proteins to form inflammasomes activate various signaling pathways and trigger IL-1  and IL-18 production (Fig. 2) (Miao et al., 2010; Gong and Shao, 2012; Suzuki et al., 2007; McCoy et al., 2010; Lei et al., 2012). According to the common function in innate immune response against microbial pathogen, we can build a hypothesis that miRNAs participate in NLRs-regulated immune response to jointly monitor pathogens and intercellular homeostasis. Although it is seldom been reported for the mutual regulatory relationships between miRNAs and NLRs signaling pathways, miRNAs regulation of NLRs signaling is new emerging phenomena.
Fig. 1. Involvement of miRNAs in RLR signaling pathway. There is mounting evidence that miR-146a and miR-155 can negatively regulate RLR signaling pathways by targeting key signaling proteins. In addition, using bioinformatics analysis, there are also many miRNAs targeted RLR signaling proteins or negative regulators for RLR signaling.
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Fig. 2. NLRs signaling pathways activation. NLRC include NOD1, NOD2, NLRC4, NLRX1, and NLRC5. NLRP consists of 14 members (NLRP1, NLRP2, NLRP3, NAIP5). NLR proteins are innate immune sensors that respond to microbial infection. Upon pathogen infection, NLRs activate caspase-1 and induce the production of active IL-1 and IL-18 by forming large complexes, called inflammasomes. In addition, activation of inflammasomes can also stimulate the inflammatory cell death program, named pyroptosis or autophagy. NLRC can also result in the activation of MAPK and NF-B to trigger apoptosis or cell survival. Some data have been revealed that miRNAs can regulate NLRs expression, such as miR-223, miR221/222 (Di Martino et al., 2013), miR-375 (Erener et al., 2013). Moreover, using bioinformatics analysis, there are also many miRNAs targeted RLR signaling proteins or negative regulators for RLR signaling.
Bauernfeind et al. (2012) investigated and found that NLRP3, NLRs protein, which mediates caspase-1 activation in response to pathogen, was regulated by miR-223, they found that miR-223 as a negative regulator of NLRP3 to reduced NLRP3 inflammasome activity (Bauernfeind et al., 2012). Furthermore, it has been recently reported that virus miRNA (EBV miR-BART15) and miR223 can target the NLRP3 -untranslated region to inhibit the NLRP3 inflammasome in non-infected cells or monocytes, respectively (Haneklaus et al., 2012). Linking with bioinformatics analysis results, it has been speculated that many miRNAs may target NLRs protein to participate in NLRs-mediated innate immune (Fig. 2). Besides miRNA-targeted NLRs, the date also can be exhibited that NLRs change miRNA expression. NOD2 specific ligands MDP can up-regulate miR-155 expression weakly in TLR2/4−/− BMMs, but NOD1 do not mediate up-regulation of miR-155 (Koch et al., 2012). In viral infection research, miR-146a, miR-23a and miR-21 whose expression was regulated by CVB3 infection were found to modulate NOD-like receptor signaling pathway via target prediction and functional analysis of differentially expressed miRNAs (Zhang, 2012). In addition, the expression of miR-129-5p that was selectively up-regulated by the NOD2-elicitor MDP led to an up-regulation of DEFB1, IRAK1, FBXW7 and IKK␥ (Nemo), indicating that miR-129-5p is a new rheostat controlling NLR-mediated responses (Häsler et al., 2012). Given that NOD2 agonist MDP and NOD1/2 agonist M-TriDAP can defend significant miR-155 expression and NF-kB activity to bacterial pathogens, Schulte et al. (2012) suggests that miR-155 is activated via NOD2-dependent pathway to ultimately inhibit proinflammatory signaling, when TLR4-based innate immune response is silent (Schulte et al., 2012). 5. Concluding remarks and future perspectives During host immune responses against pathogen infection, pattern recognition receptors (PRRs) play a critical role in contributing
toward innate immune responses. miRNAs as posttranscriptional regulators also is crucial in innate immune response during viral infection. Thus, we summarize the current knowledge and discuss the mechanisms that miRNAs utilize to regulate PRR signalingmediated innate immune in response to the pathogens and the interlinks between miRNAs and PRR signaling pathways in this review. miRNAs regulate PRR signaling pathways and control inflammatory responses by targeting PRR signaling, or negative regulators. Moreover, PRR stimulation also can trigger miRNAs expression, which in turn activates several intra-cellular signaling pathways to combat the pathogen. On the other hand, several pathogens-coded miRNA targets innate immune receptor signaling, results in abnormal immune response for their own benefit to achieve highest survival possibilities. Understanding the role of miRNAs in PRR-mediated immune regulatory network will let us better understand the host innate defense against virus infection, but will also provide us with new immune-suppressive therapies for preventing and managing more effectively the pathogen infections. In addition, whether the interplay between PRRs signaling pathways that regulates miRNA function in the innate immune response against pathogens should be determined, that further can provide a comprehensive understanding of miRNAs.
Acknowledgments We thank all of the colleagues in our lab for helpful discussion. This work was supported by financial assistance from Chinese projects from the Chinese government (31272427, 20110146110005, 2013070204020045 and B12005) and the Huanghe Yingcai project from the Wuhan government. In addition, Open Project of Hubei Key Laboratory of Animal Embryo and Molecular Breeding (2013ZD101) are greatly appreciated.
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References Abend, J.R., Ramalingam, D., Kieffer-Kwon, P., Uldrick, T.S., Yarchoan, R., Ziegelbauer, J.M., 2012. KSHV microRNAs target two components of the TLR/IL-1R signaling cascade, IRAK1 and MyD88, to reduce inflammatory cytokine expression. J. Virol. 86, 11163–11674. Liston, A., Papadopoulou, A.S., Danso-Abeam, D., Dooley, J., 2012. MicroRNA-29 in the adaptive immune system: setting the threshold. Cell. Mol. Life Sci. 69, 3533–3541. Akira, S., Uematsu, S., Takeuchi, O., 2006. Pathogen recognition and innate immunity. Cell 124, 783–801. ´ Antosz, H., Choroszynska, D., 2013. Negative regulation of Toll-like receptor signalling. Postepy Hig. Med. Dosw. 67, 339–350 (Online). Bartel, D.P., 2009. MicroRNAs: target recognition and regulatory functions. Cell 136 (2), 215–233. Bauernfeind, F., Rieger, A., Schildberg, F.A., Knolle, P.A., Schmid-Burgk, J.L., Hornung, V.2012., 2012. NLRP3 inflammasome activity is negatively controlled by miR223. J. Immunol. 189 (8), 4175–4181. Benakanakere, M.R., Li, Q., Eskan, M.A., Singh, A.V., Zhao, J., Galicia, J.C., Stathopoulou, P., Knudsen, T.B., Kinane, D.F., 2009. Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J. Biol. Chem. 284 (34), 23107–23115. Bi, Y., Liu, G., Yang, R., 2009. NAs: novel regulators during the immune response. J. Cell. Physiol. 218 (3), 467–472. Brint, E.K., Xu, D., Liu, H., Dunne, A., McKenzie, A.N., O’Neill, L.A., Liew, F.Y., 2004. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat. Immunol. 5 (4), 373–379. Buggele, W.A., Johnson, K.E., Horvath, C.M., 2012. Influenza A virus infection of human respiratory cells induces primary microRNA expression. J. Biol. Chem. 287 (37), 31027–31040. Chen, X.M., Splinter, P.L., O’Hara, S.P., LaRusso, N.F., 2007. A cellular micro-RNA, let7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J. Biol. Chem. 282 (39), 28929–28938. Chen, C.Z., Li, L., Lodish, H.F., Bartel, D.P., 2004. MicroRNAs modulate hematopoietic lineage differentiation. Science 303 (5654), 83–86. Di Martino, M.T., Gullà, A., Cantafio, M.E., Lionetti, M., Leone, E., Amodio, N., Guzzi, P.H., Foresta, U., Conforti, F., Cannataro, M., Neri, A., Giordano, A., Tagliaferri, P., Tassone, P., 2013. In vitro and in vivo anti-tumor activity of miR-221/222 inhibitors in multiple myeloma. Oncotarget 4 (2), 242–255. Erener, S., Mojibian, M., Fox, J.K., Denroche, H.C., Kieffer, T.J., 2013. Circulating miR375 as a biomarker of -cell death and diabetes in mice. Endocrinology 154 (2), 603–608. Fujita, T., Onoguchi, K., Onomoto, K., Hirai, R., Yoneyama, M., 2007. Triggering antiviral response by RIG-I-related RNA helicases? Biochimie 89 (6-7), 754–760. Galli, R., Paone, A., Fabbri, M., Zanesi, N., Calore, F., Cascione, L., Acunzo, M., Stoppacciaro, A., Tubaro, A., Lovat, F., Gasparini, P., Fadda, P., Alder, H., Volinia, S., Filippini, A., Ziparo, E., Riccioli, A., Croce, C.M., 2013. Toll-like receptor 3 (TLR3) activation induces microRNA-dependent re-expression of functional RAR and tumor regression. Proc. Natl. Acad. Sci. U.S.A. 110 (24), 9812–9817. Gong, Y.N., Shao, F., 2012. Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation. Protein Cell 3 (2), 98–105. Grimson, A., Kai-How Farh, K., Johnston, W.K., Garrett-Engele, P., Lim, L.P., Bartel, D.P., 2007. MicroRNA targeting specificity in mammals: determinants beyond seed pairing molecular. Cell 27, 91–105. Haneklaus, M., Gerlic, M., Kurowska-Stolarska, M., Rainey, A.A., Pich, D., McInnes, I.B., Hammerschmidt, W., O’Neill, L.A., Masters, S.L.2012., 2012. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1 production. J. Immunol. 189 (8), 3795–3799. Häsler, R., Jacobs, G., Till, A., Grabe, N., Cordes, C., Nikolaus, S., Lao, K., Schreiber, S., Rosenstiel, P., 2012. Microbial pattern recognition causes distinct functional micro-RNA signatures in primary human monocytes. PLoS ONE 7 (2), e31151. Hou, J., Wang, P., Lin, L., Liu, X., Ma, F., An, H., Wang, Z., Cao, X., 2009. MicroRNA146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J. Immunol. 183 (3), 2150–2158. Koch, M., Mollenkopf, H.J., Klemm, U., Meyer, T.F., 2012. Induction of microRNA155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis. Proc. Natl. Acad. Sci. U.S.A. 109 (19), E1153–E1162. Lei, Y., Wen, H., Yu, Y., Taxman, D.J., Zhang, L., Widman, D.G., Swanson, K.V., Wen, K.W., Damania, B., Moore, C.B., Giguère, P.M., Siderovski, D.P., Hiscott, J., Razani, B., Semenkovich, C.F., Chen, X., Ting, J.P., 2012. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36 (6), 933–946. Lewis, B.P., Burge, C.B., Bartel, D.P., 2005. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120 (1), 15–20. Li, Y., Chan, E.Y., Li, J., Ni, C., Peng, X., Rosenzweig, E., Tumpey, T.M., Katze, M.G., 2010. MicroRNA expression and virulence in pandemic influenza virus-infected mice. J. Virol. 84 (6), 3023–3032. Liao, Y., Du, X., Lönnerdal, B., 2010. miR-214 regulates lactoferrin expression and pro-apoptotic function in mammary epithelial cells. J. Nutr. 140 (9), 1552–1556. Liew, F.Y., Xu, D., Brint, E.K., O’Neill, L.A., 2005. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5 (6), 446–458. Liu, G., Friggeri, A., Yang, Y., Park, Y.J., Tsuruta, Y., Abraham, E., 2009. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine
5
macrophage inflammatory responses. Proc. Natl. Acad. Sci. U.S.A. 106 (37), 15819–15824. Liu, X., Zhan, Z., Xu, L., Ma, F., Li, D., Guo, Z., Li, N., Cao, X., 2010. MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKII␣. J. Immunol. 185 (12), 7244–7251. Lu, L.F., Liston, A., 2009. MicroRNA in the immune system, microRNA as an immune system. Immunology 127 (3), 291–298. McCoy, A.J., Koizumi, Y., Higa, N., Suzuki, T., 2010. Differential regulation of caspase1 activation via NLRP3/NLRC4 inflammasomes mediated by aerolysin and type III secretion system during Aeromonas veronii infection. J. Immunol. 185 (11), 7077–7084. Meylan, E., Tschopp, J., Karin, M., 2006. Intracellular pattern recognition receptors in the host response. Nature 442 (7098), 39–44. Miao, E.A., Mao, D.P., Yudkovsky, N., Bonneau, R., Lorang, C.G., Warren, S.E., Leaf, I.A., Aderem, A., 2010. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc. Natl. Acad. Sci. U.S.A. 107 (7), 3076–3080. Nasirudeen, A.M., Wong, H.H., Thien, P., Xu, S., Lam, K.P., Liu, D.X., 2011. RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. PLoS Negl. Trop. Dis. 5 (1), e926. O’Neill, L.A., Sheedy, F.J., McCoy, C.E., 2011. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat. Rev. Immunol. 11 (3), 163–175. Ouda, R., Onomoto, K., Takahasi, K., Edwards, M.R., Kato, H., Yoneyama, M., Fujita, T., 2011. RIG-I-inducible miR-23b inhibits infections by minor group rhinoviruses through down-regulation of the receptor VLDLR. J. Biol. Chem. 286 (29), 26210–26219. Pedersen, I.M., Cheng, G., Wieland, S., Volinia, S., Croce, C.M., Chisari, F.V., David, M., 2007. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449 (7164), 919–922. Rämet, M., Korppi, M., Hallman, M., 2011. Pattern recognition receptors and genetic risk for RSV infection: value for clinical decision-making? Pediatr. Pulmonol. 46 (2), 101–110. Schulte, L.N., Westermann, A.J., Vogel, J., 2012. Differential activation and functional specialization of miR-146 and miR-155 in innate immune sensing. Nucleic Acids Res. (Epub ahead of print). Sheedy, F.J., Palsson-McDermott, E., Hennessy, E.J., Martin, C., O’Leary, J.J., Ruan, Q., Johnson, D.S., Chen, Y., O’Neill, L.A., 2010. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat. Immunol. 11 (2), 141–147. Silva, L.F., Jones, C., 2012. Two microRNAs encoded within the bovine herpesvirus 1 latency-related gene promote cell survival by interacting with RIG-I and stimulating NF-B-dependent transcription and beta interferon signaling pathways. J. Virol. 86 (3), 1670–1682. Stack, J., Haga, I.R., Schröder, M., Bartlett, N.W., Maloney, G., Reading, P.C., Fitzgerald, K.A., Smith, G.L., Bowie, A.G., 2005. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J. Exp. Med. 201 (6), 1007–1018. Sullivan, C.S., Ganem, D., 2005. MicroRNAs and viral infection. Mol. Cell 20 (1), 3–7. Suzuki, T., Franchi, L., Toma, C., Ashida, H., Ogawa, M., Yoshikawa, Y., Mimuro, H., ˜ G., 2007. Differential regulation of caspaseInohara, N., Sasakawa, C., Nunez, 1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3 (8), e111. Swaminathan, G., Rossi, F., Sierra, L.J., Gupta, A., Navas-Martín, S., Martín-García, J., 2012. A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages. PLoS Pathog. 8 (9), e1002937. Taganov, K.D., Boldin, M.P., Chang, K.J., Baltimore, D., 2006. NF-{kappa} B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. U.S.A. 103, 12481–12486. Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T.W., Taniguchi, T., 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434 (7030), 243–249. Takeuchi, O., Akira, S., 2010. Pattern recognition receptors and inflammation. Cell 140, 805–820. Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R.L., Akira, S., 2002. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169 (1), 10–14. Tuddenham, L., Pfeffer, S., 2011. Roles and regulation of microRNAs in cytomegalovirus infection. Biochim. Biophys. Acta 1809 (11–12), 613–622. Vasudevan, S., Tong, Y., Steitz, J.A., 2007. Switching from repression to activation: microRNAs can up-regulate translation. Science 318 (5858), 1931–1934. Wang, P., Hou, J., Lin, L., Wang, C., Liu, X., Li, D., Ma, F., Wang, Z., Cao, X., 2010. Inducible microRNA-155 feedback promotes RIG-I-dependent type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J. Immunol. 185 (10), 6226–6233. Williams, A., Flavell, R.A., Eisenbarth, S.C., 2010. The role of NOD-like receptors in shaping adaptive immunity. Curr. Opin. Immunol. 22 (1), 34–40. Xiao, B., Liu, Z., Li, B.S., Tang, B., Li, W., Guo, G., Shi, Y., Wang, F., Wu, Y., Tong, W.D., Guo, H., Mao, X.H., Zou, Q.M., 2009. Induction of microRNA-155 during Helicobacter pylori infection and its negative regulatory role in the inflammatory response. J. Infect. Dis. 200 (6), 916–925. Yoneyama, M., Fujita, T., 2007. Function of RIG-I-like receptors in antiviral innate immunity. J. Biol. Chem. 282 (21), 15315–15318. Yoneyama, M., Fujita, T., 2009. RNA recognition and signal transduction by RIG-I-like receptors. Immunol. Rev. 227 (1), 54–65.
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Yoneyama, M., Kikuchi, M., Natsukawa, T., Shinobu, N., Imaizumi, T., Miyagishi, M., Taira, K., Akira, S., Fujita, T., 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5 (7), 730–737. Yun, J.J., Tsao, M.S., Der, S.D., 2011. Differential utilization of NF-kappaB RELA and RELB in response to extracellular versus intracellular polyIC stimulation in HT1080 cells. BMC Immunol. 12, 15.
Zhang, Q., Xiao, Z., He, F., Zou, J., Wu, S., Liu, Z., 2012. MicroRNAs regulate the pathogenesis of CVB3-induced viral myocarditis. Intervirology (Epub ahead of print). Zhao, Y., Srivastava, D., 2007. A developmental view of microRNA function. Trends Biochem. Sci. 32, 189–197. Zhou, Y., Wang, X., Liu, M., Hu, Q., Song, L., Ye, L., Zhou, D., Ho, W., 2010. A critical function of toll-like receptor-3 in the induction of anti-human immunodeficiency virus activities in macrophages. Immunology 131 (1), 40–49.
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Virus Research journal homepage: www.elsevier.com/locate/virusres
Review
Interplay between microRNAs and host pathogen recognition receptors (PRRs) signaling pathways in response to viral infection Ao Zhou a , Shuaifeng Li a , Junjing Wu b , Faheem Ahmed Khan a , Shujun Zhang a,∗ a Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China b Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Institute of Animal Husbandry and Veterinary, Hubei Provincial Academy of Agricultural Sciences, Wuhan 430064, China
a r t i c l e
i n f o
Article history: Received 20 October 2013 Received in revised form 17 January 2014 Accepted 17 January 2014 Keywords: PRRs PAMP MicroRNAs Innate immune response
a b s t r a c t Antimicrobial response is greatly influenced by microRNAs (miRNAs) which are the important posttranscriptional regulators of gene expression. Simultaneously, host pathogen recognition receptors (PRRs) engaged by pathogen-associated molecular patterns (PAMPs) also play critical roles in activating innate immunity against microbial infection. Emerging evidences suggest that the interaction between microbial-regulated miRNAs and important PRRs signaling pathways influence host immune response to microbial pathogens. In this manuscript, we describe the roles of miRNAs in virus-regulated innate immune pathways and the crosstalk between miRNAs and PRRs, further breaking out the mechanistic dissection of miRNAs–PRRs in viral infection and the development of the prognosis of disease and novel miRNA-therapeutic strategies targeting immunity. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miRNAs and Toll-like receptors signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miRNAs and cytoplasmic RIG-I-like receptors (RLRs) signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . miRNAs participate in NOD-like receptors (NLRs)-mediated innate immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Host pathogen recognition receptors (PRRs) which including Toll-like receptors (TLRs), RIG-I-like receptors (RIGs), Nod-like receptors (NLRs) and C-type lectin receptors (CLRs) are essential for the survival of the microorganism and are also critical in triggering innate immune defenses through binding to pathogenassociated molecular patterns (PAMPs), which leads to activation of intracellular signaling pathways and distinct anti-pathogen responses (Meylan et al., 7098; Rämet et al., 2011). Once PRRs signaling pathways are activated, host can trigger the production of pro-inflammatory cytokines and type 1 interferon (IFN) to inhibit viral replication (Takaoka et al., 2005; Yun et al., 2011). PRRs are expressed in macrophages, Dendritic cells (DCs), and
∗ Corresponding author. Tel.: +86 027 87281813; fax: +86 027 87281813. E-mail address: [email protected] (S. Zhang). 0168-1702/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.virusres.2014.01.019
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various nonprofessional immune cells. In addition, each member of PRRs reacts with specific PAMPs to trigger the corresponding downstream signaling events and eventually induce inflammation, innate immunity, even adaptive immune response (Takeuchi and Akira, 2010).miRNAs are highly conserved, endogenous noncoding RNA molecules, which regulate post-transcriptional gene expression to prevent protein accumulation. It has been shown that miRNAs regulate a wide range of critical physiologic and pathological processes, including cellular proliferation and differentiation, apoptosis and inflammation by inducing mRNAs degradation or translational repression of target genes (Zhao and Srivastava, 2007; Bartel, 2009). In rare cases, miRNA can also act as positive regulator when bound together with other 3 UTR binding complex (Vasudevan et al., 2007), for instance, miR-214 regulates the expression of lactoferrin that mediated pro-apoptotic activities in mammary epithelial cells (Liao et al., 2010). Adrian et al. (2012) summarized that MiR-29 family play an important role in adaptive immune system for setting the threshold in infection-associated
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thymic involution, helper T cell differentiation and lymphocyte oncogenesis (Adrian et al., 2012). In addition to participating in physiologic and pathological processes, an increasing number of studies suggest that miRNAs play pivotal roles in the regulation of viral infections (Sullivan and Ganem, 2005). The data demonstrates that miRNAs can not only control host gene expression and affect immune cell development and function, but also regulates the viral life cycle to directly interfere viral replication. MiR-323, miR-491 and miR-654 inhibit H1N1 influenza A virus replication via targeting the PB1 gene (Li et al., 2010), whereas miR-196 and miR-296 regulate type 1 interferon-associated pathways to attenuate viral replication in liver cells (Pedersen et al., 2007). Tuddenham and Pfeffer (2011) had also summarized that at least 14 mature miRNAs encoded by cytomegalovirus and their targets in viral and host cells (Tuddenham and Pfeffer, 2011). MiR-7, miR-187, miR200c, or miR-1275 were first shown to be involved in infection with two influenza A virus strains, A/Udorn/72 and A/WSN/33 or cellular antiviral responses (Buggele et al., 2012). Although increasing evidence shows that miRNAs are involved in host innate immune responses to regulate virus infection (Lu and Liston, 2009; Bi et al., 2009), the exact mechanisms to explain the role of miRNAs in host immune response to viral infection still needs to be unveiled. In addition, the nature of correlation between miRNAs, PRRs signaling pathways and innate antiviral immune is just beginning to be explored and needs future investigation. In this review, we will summarize and explore the roles of miRNAs in the regulation of the innate immune response. We will also discuss the crosstalk between miRNAs and PRRs signaling pathways in response to viral infection.
2. miRNAs and Toll-like receptors signaling pathway As key PRRs, Toll-like receptors have important roles in host innate immune responses against microbial pathogen infections via mediating activation of the transcription factor NF-B or regulating expression of type 1 interferon (Takeuchi et al., 2002; Akira et al., 2006). In turn, TLR-activates downstream signals which can modulate TLR signal transduction by interacting with upstream signaling to maintain immunological balance (Brint et al., 2004; Liew et al., 2005). TLR signaling pathways are divergent in two parts: MyD88dependent and MyD88-independent pathways. Although there is some data that portrays the interaction between TLRs signaling pathways and miRNAs that regulates virus replication and some virus also utilize the relationship between them to evade host immune responses, the exact mechanisms are not largely known. The insights gained in relative studies support the idea that miRNAs act as a key regulator of gene expression to involve in TLRmediated innate immune response (O’Neill et al., 2011). Taganov et al. (2006) had found that miR-146, miR-132 and miR-155 were significantly up-regulated in response to lipopolysaccharide (LPS) as TLR4 modulator, indicating that miRNAs have an important role in mammalian response to micro-organisms infection (Taganov et al., 2006). The data given by Liu et al. (2009) suggested that miR-147 could significantly attenuated LPS stimulated TNF-␣ and IL-6 production of TLR induced inflammatory responses, whereas its knockdown enhanced LPS and poly (I:C) induced TNF␣ and IL-6 expression, indicating that miR-147 represses TLR4 and TLR3 induced inflammatory responses. In addition, miRNAs also can target TLR4 or key TLR signaling proteins to regulate TLR-mediated innate immune in response to pathogen infection. MiR-223 was predicted as an important candidate to regulate TLR3 and TLR4 expression (Chen et al., 5654). Moreover, the finding had revealed that let-7i regulated TLR4 expression through translational repression and triggered epithelial innate immune against Cryptosporidium parvum infection (Chen et al., 2007), Whereas
TLR2 is a potential target for miR-105 through in silico analysis and the interaction between miR-105 and TLR2 can result in the down-regulation of cytokine production and suppress excessive inflammation (Benakanakere et al., 2009). There are also other evidences suggesting that miR-21 was a negative regulator for TLR4 signaling to activate NF-B and decrease IL-10 production by targeting a pro-inflammatory protein PDCD4 (Sheedy et al., 2010). MiR-146/152 could regulate TLR-triggered innate immune response and Ag-presenting capacity of DCs by targeting CaMKII␣ that enabled upgrade TLR-induced production of pro-inflammatory cytokines (Liu et al., 2010). Especially, viral-encoded miRNA have been shown to autoregulate viral mRNA or deregulate cellular mRNAs, but the function of the major viral miRNAs still remains to be determined. Insight into the pathogenic nature of these viruses’ miRNAs in innate immunity will provide new therapeutic strategies against virus infection. For example, a date from Abend et al. suggests that KSHV-encoded miRNAs (miR-K5 and miR-K9) expression results in down regulation of MyD88 and IRAK1, which are vital molecules in TLR/IL-1R signaling cascade, leading to the change in virus infection (Abend et al., 2012). Accumulated information has also revealed that TLRs can induce the expression of miRNAs, which in turn regulate virus infection through targeting miRNAs-interacted genes or protein. O’Neill et al. had summarized that the expression of miRNAs was modulated by TLR signaling (O’Neill et al., 2011). Moreover, there had been more evidences that TLR-inducted miRNAs, in turn, negatively regulated TLR signaling. Upon stimulation of multiple TLRs, miR-147 can regulate murine macrophage inflammatory responses (Liu et al., 2009). Through studying the mechanisms underlying the role of TLR-3 activation on HIV replication, a group of scientists has found that activated TLR-3 highlighted the expression of cellular miRNAs to inhibit HIV replication (Zhou et al., 2010). The expression of microRNA-29b, -29c, -148b, and -152 were up-regulated under TLR3 activation by poly I:C in tumor-derived cell lines and primary tumors (Galli et al., 2013), indicating that relational miRNAs may have anti-viral function. In addition, miR-155 has been identified as an anti-HIV-1 factor that results in inhibiting HIV-1 replication (Swaminathan et al., 2012). Although some findings were existed to support that miRNAs is pivotal in antiviral immune response by a variety of strategies, this function triggered by TLR signaling pathway still remains unclear. It has also been shown that negative regulation of TLR signaling is essential for limiting inflammation and benefiting viral replication (Stack et al., 2005). Thus, we speculate that when TLR signaling inhibitors are targeted by miRNAs, TLRs induce inflammatory cells to recognize invading microbial pathogens and activate innate immune responses to block viral infection, although there is presently little experimental evidence to support that hypothesis. Through bioinformatic analyses and experimental approaches, it has been known that a number of genes can be targeted by miRNAs (Lewis et al., 2005), and it is also possible that negative regulators of TLRs such as RP105, ST2L and IRAK-M (Antosz ´ and Choroszynska, 2013) can be targeted by miRNAs which intern enhances TLR signaling triggered immune responses.
3. miRNAs and cytoplasmic RIG-I-like receptors (RLRs) signaling pathway RIG-I-like receptors (RLRs) has three DExD/H box helicases, including retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated antigen 5 (MDA5) and laboratory of genetics and physiolpgy2 (LGP2) that positively regulate the RIGI/MDA5 mediated antiviral responses and can potentiate INF production during viral infection. But its precise role in regulating
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RLRs signal remains to be determined (Yoneyama et al., 2004; Yoneyama and Fujita, 2009). RLRs are key regulatory factors to induce type 1 interferon (IFN) mediated innate immunity to suppress viral replication (Yoneyama and Fujita, 2007; Fujita et al., 2007; Nasirudeen et al., 2011). In addition, it has become increasingly evident that virus also can regulate RLR-mediated innate immune by miRNAs and the role of miRNAs in regulating RLR signaling pathway are to be identified and understood. Recently, a report states that miR-146a was a negative regulator of RIG-I antiviral pathway. miR-146a can impair RIG-I signaling and down-regulate RIG-I-triggered type 1 IFN production to promote VSV replication in macrophages by targeting TRAF6, IRAK1 and IRAK2, which were associated with important regulators in RIG-I signaling pathway (Hou et al., 2009). miRNA-155 was able to target IKK and FADD, which were important protein in RLR signaling pathway, and over-expression of miR-155 down-regulated these target protein via mRNA degradation or translation repression (Xiao et al., 2009). In addition, it has been identified that virusencoded miRNAs are expressed and involved in virus infection to influence RIG-I antiviral pathway and host immune response. The results presented by Silva and Jones (2012) suggested that bICP0 protein expression and productive infection were interfered by BHV-1 miRNAs, which expressed during latency and stimulated the RIG-1 signaling pathway that correlated with activated type I IFN signaling, although they have no valid evidence to depict the mechanism how the LR-encoded miRNAs were recognized by RIG-I (Silva and Jones, 2012). Apart from miRNA-activated RIGI signaling, RIG- I signaling also regulates miRNA abundance in response to infection with virus. miR-155 as an important immune regulator was induced in macrophages through RIG-I/JNK/NF-kBdependent pathway, resulting in promoting type I IFN signaling and suppressing viral replication (Wang et al., 2010). Strikingly, another key player in innate immunity, miR-146 was up-regulated during virus infection in macrophages through RIG-I-NF-kB-dependent and TLR-MyD88-independent pathways, but inducible miR-146
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negatively inhibits RIG-I-dependent type I IFN signaling production, leading to increase virus replication (Hou et al., 2009). New data had been emerged that RIG-I mediated signaling was able to up-regulate 37miRNAs expression and RIG-I-inducible miR-23b significantly suppressed the entry of rhinovirus 1B (RV1B) though targeting VLDLR as RV1B receptor, but not post-entry viral replication (Ouda et al., 2011). Bioinformatic analysis of the 3 untranslated regions (UTRs) of genes involved in RLR signaling pathway using the prediction program TargetScan (http://www.targetscan.org/) and miRNAda (Grimson et al., 2007) indicated that many miRNAs can regulate RLR signaling pathway by targeting key signaling proteins or negative regulators for RLR signaling (Fig. 1). However, when virus infection, the role of miRNAs involved in RLR signaling pathway regulating immune response still needs to be confirmed via experimental evidence. 4. miRNAs participate in NOD-like receptors (NLRs)-mediated innate immune response It has been demonstrated that Cytoplasmic NLRs are important regulators of innate and adaptive immune responses in microbial pathogenesis and mammalian immunity (Miao et al., 2010; Williams et al., 2010). NLRs proteins, innate immune sensors against microbial infection, combining with some signaling proteins to form inflammasomes activate various signaling pathways and trigger IL-1  and IL-18 production (Fig. 2) (Miao et al., 2010; Gong and Shao, 2012; Suzuki et al., 2007; McCoy et al., 2010; Lei et al., 2012). According to the common function in innate immune response against microbial pathogen, we can build a hypothesis that miRNAs participate in NLRs-regulated immune response to jointly monitor pathogens and intercellular homeostasis. Although it is seldom been reported for the mutual regulatory relationships between miRNAs and NLRs signaling pathways, miRNAs regulation of NLRs signaling is new emerging phenomena.
Fig. 1. Involvement of miRNAs in RLR signaling pathway. There is mounting evidence that miR-146a and miR-155 can negatively regulate RLR signaling pathways by targeting key signaling proteins. In addition, using bioinformatics analysis, there are also many miRNAs targeted RLR signaling proteins or negative regulators for RLR signaling.
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Fig. 2. NLRs signaling pathways activation. NLRC include NOD1, NOD2, NLRC4, NLRX1, and NLRC5. NLRP consists of 14 members (NLRP1, NLRP2, NLRP3, NAIP5). NLR proteins are innate immune sensors that respond to microbial infection. Upon pathogen infection, NLRs activate caspase-1 and induce the production of active IL-1 and IL-18 by forming large complexes, called inflammasomes. In addition, activation of inflammasomes can also stimulate the inflammatory cell death program, named pyroptosis or autophagy. NLRC can also result in the activation of MAPK and NF-B to trigger apoptosis or cell survival. Some data have been revealed that miRNAs can regulate NLRs expression, such as miR-223, miR221/222 (Di Martino et al., 2013), miR-375 (Erener et al., 2013). Moreover, using bioinformatics analysis, there are also many miRNAs targeted RLR signaling proteins or negative regulators for RLR signaling.
Bauernfeind et al. (2012) investigated and found that NLRP3, NLRs protein, which mediates caspase-1 activation in response to pathogen, was regulated by miR-223, they found that miR-223 as a negative regulator of NLRP3 to reduced NLRP3 inflammasome activity (Bauernfeind et al., 2012). Furthermore, it has been recently reported that virus miRNA (EBV miR-BART15) and miR223 can target the NLRP3 -untranslated region to inhibit the NLRP3 inflammasome in non-infected cells or monocytes, respectively (Haneklaus et al., 2012). Linking with bioinformatics analysis results, it has been speculated that many miRNAs may target NLRs protein to participate in NLRs-mediated innate immune (Fig. 2). Besides miRNA-targeted NLRs, the date also can be exhibited that NLRs change miRNA expression. NOD2 specific ligands MDP can up-regulate miR-155 expression weakly in TLR2/4−/− BMMs, but NOD1 do not mediate up-regulation of miR-155 (Koch et al., 2012). In viral infection research, miR-146a, miR-23a and miR-21 whose expression was regulated by CVB3 infection were found to modulate NOD-like receptor signaling pathway via target prediction and functional analysis of differentially expressed miRNAs (Zhang, 2012). In addition, the expression of miR-129-5p that was selectively up-regulated by the NOD2-elicitor MDP led to an up-regulation of DEFB1, IRAK1, FBXW7 and IKK␥ (Nemo), indicating that miR-129-5p is a new rheostat controlling NLR-mediated responses (Häsler et al., 2012). Given that NOD2 agonist MDP and NOD1/2 agonist M-TriDAP can defend significant miR-155 expression and NF-kB activity to bacterial pathogens, Schulte et al. (2012) suggests that miR-155 is activated via NOD2-dependent pathway to ultimately inhibit proinflammatory signaling, when TLR4-based innate immune response is silent (Schulte et al., 2012). 5. Concluding remarks and future perspectives During host immune responses against pathogen infection, pattern recognition receptors (PRRs) play a critical role in contributing
toward innate immune responses. miRNAs as posttranscriptional regulators also is crucial in innate immune response during viral infection. Thus, we summarize the current knowledge and discuss the mechanisms that miRNAs utilize to regulate PRR signalingmediated innate immune in response to the pathogens and the interlinks between miRNAs and PRR signaling pathways in this review. miRNAs regulate PRR signaling pathways and control inflammatory responses by targeting PRR signaling, or negative regulators. Moreover, PRR stimulation also can trigger miRNAs expression, which in turn activates several intra-cellular signaling pathways to combat the pathogen. On the other hand, several pathogens-coded miRNA targets innate immune receptor signaling, results in abnormal immune response for their own benefit to achieve highest survival possibilities. Understanding the role of miRNAs in PRR-mediated immune regulatory network will let us better understand the host innate defense against virus infection, but will also provide us with new immune-suppressive therapies for preventing and managing more effectively the pathogen infections. In addition, whether the interplay between PRRs signaling pathways that regulates miRNA function in the innate immune response against pathogens should be determined, that further can provide a comprehensive understanding of miRNAs.
Acknowledgments We thank all of the colleagues in our lab for helpful discussion. This work was supported by financial assistance from Chinese projects from the Chinese government (31272427, 20110146110005, 2013070204020045 and B12005) and the Huanghe Yingcai project from the Wuhan government. In addition, Open Project of Hubei Key Laboratory of Animal Embryo and Molecular Breeding (2013ZD101) are greatly appreciated.
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References Abend, J.R., Ramalingam, D., Kieffer-Kwon, P., Uldrick, T.S., Yarchoan, R., Ziegelbauer, J.M., 2012. KSHV microRNAs target two components of the TLR/IL-1R signaling cascade, IRAK1 and MyD88, to reduce inflammatory cytokine expression. J. Virol. 86, 11163–11674. Liston, A., Papadopoulou, A.S., Danso-Abeam, D., Dooley, J., 2012. MicroRNA-29 in the adaptive immune system: setting the threshold. Cell. Mol. Life Sci. 69, 3533–3541. Akira, S., Uematsu, S., Takeuchi, O., 2006. Pathogen recognition and innate immunity. Cell 124, 783–801. ´ Antosz, H., Choroszynska, D., 2013. Negative regulation of Toll-like receptor signalling. Postepy Hig. Med. Dosw. 67, 339–350 (Online). Bartel, D.P., 2009. MicroRNAs: target recognition and regulatory functions. Cell 136 (2), 215–233. Bauernfeind, F., Rieger, A., Schildberg, F.A., Knolle, P.A., Schmid-Burgk, J.L., Hornung, V.2012., 2012. NLRP3 inflammasome activity is negatively controlled by miR223. J. Immunol. 189 (8), 4175–4181. Benakanakere, M.R., Li, Q., Eskan, M.A., Singh, A.V., Zhao, J., Galicia, J.C., Stathopoulou, P., Knudsen, T.B., Kinane, D.F., 2009. Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J. Biol. Chem. 284 (34), 23107–23115. Bi, Y., Liu, G., Yang, R., 2009. NAs: novel regulators during the immune response. J. Cell. Physiol. 218 (3), 467–472. Brint, E.K., Xu, D., Liu, H., Dunne, A., McKenzie, A.N., O’Neill, L.A., Liew, F.Y., 2004. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat. Immunol. 5 (4), 373–379. Buggele, W.A., Johnson, K.E., Horvath, C.M., 2012. Influenza A virus infection of human respiratory cells induces primary microRNA expression. J. Biol. Chem. 287 (37), 31027–31040. Chen, X.M., Splinter, P.L., O’Hara, S.P., LaRusso, N.F., 2007. A cellular micro-RNA, let7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J. Biol. Chem. 282 (39), 28929–28938. Chen, C.Z., Li, L., Lodish, H.F., Bartel, D.P., 2004. MicroRNAs modulate hematopoietic lineage differentiation. Science 303 (5654), 83–86. Di Martino, M.T., Gullà, A., Cantafio, M.E., Lionetti, M., Leone, E., Amodio, N., Guzzi, P.H., Foresta, U., Conforti, F., Cannataro, M., Neri, A., Giordano, A., Tagliaferri, P., Tassone, P., 2013. In vitro and in vivo anti-tumor activity of miR-221/222 inhibitors in multiple myeloma. Oncotarget 4 (2), 242–255. Erener, S., Mojibian, M., Fox, J.K., Denroche, H.C., Kieffer, T.J., 2013. Circulating miR375 as a biomarker of -cell death and diabetes in mice. Endocrinology 154 (2), 603–608. Fujita, T., Onoguchi, K., Onomoto, K., Hirai, R., Yoneyama, M., 2007. Triggering antiviral response by RIG-I-related RNA helicases? Biochimie 89 (6-7), 754–760. Galli, R., Paone, A., Fabbri, M., Zanesi, N., Calore, F., Cascione, L., Acunzo, M., Stoppacciaro, A., Tubaro, A., Lovat, F., Gasparini, P., Fadda, P., Alder, H., Volinia, S., Filippini, A., Ziparo, E., Riccioli, A., Croce, C.M., 2013. Toll-like receptor 3 (TLR3) activation induces microRNA-dependent re-expression of functional RAR and tumor regression. Proc. Natl. Acad. Sci. U.S.A. 110 (24), 9812–9817. Gong, Y.N., Shao, F., 2012. Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation. Protein Cell 3 (2), 98–105. Grimson, A., Kai-How Farh, K., Johnston, W.K., Garrett-Engele, P., Lim, L.P., Bartel, D.P., 2007. MicroRNA targeting specificity in mammals: determinants beyond seed pairing molecular. Cell 27, 91–105. Haneklaus, M., Gerlic, M., Kurowska-Stolarska, M., Rainey, A.A., Pich, D., McInnes, I.B., Hammerschmidt, W., O’Neill, L.A., Masters, S.L.2012., 2012. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1 production. J. Immunol. 189 (8), 3795–3799. Häsler, R., Jacobs, G., Till, A., Grabe, N., Cordes, C., Nikolaus, S., Lao, K., Schreiber, S., Rosenstiel, P., 2012. Microbial pattern recognition causes distinct functional micro-RNA signatures in primary human monocytes. PLoS ONE 7 (2), e31151. Hou, J., Wang, P., Lin, L., Liu, X., Ma, F., An, H., Wang, Z., Cao, X., 2009. MicroRNA146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J. Immunol. 183 (3), 2150–2158. Koch, M., Mollenkopf, H.J., Klemm, U., Meyer, T.F., 2012. Induction of microRNA155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis. Proc. Natl. Acad. Sci. U.S.A. 109 (19), E1153–E1162. Lei, Y., Wen, H., Yu, Y., Taxman, D.J., Zhang, L., Widman, D.G., Swanson, K.V., Wen, K.W., Damania, B., Moore, C.B., Giguère, P.M., Siderovski, D.P., Hiscott, J., Razani, B., Semenkovich, C.F., Chen, X., Ting, J.P., 2012. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36 (6), 933–946. Lewis, B.P., Burge, C.B., Bartel, D.P., 2005. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120 (1), 15–20. Li, Y., Chan, E.Y., Li, J., Ni, C., Peng, X., Rosenzweig, E., Tumpey, T.M., Katze, M.G., 2010. MicroRNA expression and virulence in pandemic influenza virus-infected mice. J. Virol. 84 (6), 3023–3032. Liao, Y., Du, X., Lönnerdal, B., 2010. miR-214 regulates lactoferrin expression and pro-apoptotic function in mammary epithelial cells. J. Nutr. 140 (9), 1552–1556. Liew, F.Y., Xu, D., Brint, E.K., O’Neill, L.A., 2005. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5 (6), 446–458. Liu, G., Friggeri, A., Yang, Y., Park, Y.J., Tsuruta, Y., Abraham, E., 2009. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine
5
macrophage inflammatory responses. Proc. Natl. Acad. Sci. U.S.A. 106 (37), 15819–15824. Liu, X., Zhan, Z., Xu, L., Ma, F., Li, D., Guo, Z., Li, N., Cao, X., 2010. MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKII␣. J. Immunol. 185 (12), 7244–7251. Lu, L.F., Liston, A., 2009. MicroRNA in the immune system, microRNA as an immune system. Immunology 127 (3), 291–298. McCoy, A.J., Koizumi, Y., Higa, N., Suzuki, T., 2010. Differential regulation of caspase1 activation via NLRP3/NLRC4 inflammasomes mediated by aerolysin and type III secretion system during Aeromonas veronii infection. J. Immunol. 185 (11), 7077–7084. Meylan, E., Tschopp, J., Karin, M., 2006. Intracellular pattern recognition receptors in the host response. Nature 442 (7098), 39–44. Miao, E.A., Mao, D.P., Yudkovsky, N., Bonneau, R., Lorang, C.G., Warren, S.E., Leaf, I.A., Aderem, A., 2010. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc. Natl. Acad. Sci. U.S.A. 107 (7), 3076–3080. Nasirudeen, A.M., Wong, H.H., Thien, P., Xu, S., Lam, K.P., Liu, D.X., 2011. RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. PLoS Negl. Trop. Dis. 5 (1), e926. O’Neill, L.A., Sheedy, F.J., McCoy, C.E., 2011. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat. Rev. Immunol. 11 (3), 163–175. Ouda, R., Onomoto, K., Takahasi, K., Edwards, M.R., Kato, H., Yoneyama, M., Fujita, T., 2011. RIG-I-inducible miR-23b inhibits infections by minor group rhinoviruses through down-regulation of the receptor VLDLR. J. Biol. Chem. 286 (29), 26210–26219. Pedersen, I.M., Cheng, G., Wieland, S., Volinia, S., Croce, C.M., Chisari, F.V., David, M., 2007. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449 (7164), 919–922. Rämet, M., Korppi, M., Hallman, M., 2011. Pattern recognition receptors and genetic risk for RSV infection: value for clinical decision-making? Pediatr. Pulmonol. 46 (2), 101–110. Schulte, L.N., Westermann, A.J., Vogel, J., 2012. Differential activation and functional specialization of miR-146 and miR-155 in innate immune sensing. Nucleic Acids Res. (Epub ahead of print). Sheedy, F.J., Palsson-McDermott, E., Hennessy, E.J., Martin, C., O’Leary, J.J., Ruan, Q., Johnson, D.S., Chen, Y., O’Neill, L.A., 2010. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat. Immunol. 11 (2), 141–147. Silva, L.F., Jones, C., 2012. Two microRNAs encoded within the bovine herpesvirus 1 latency-related gene promote cell survival by interacting with RIG-I and stimulating NF-B-dependent transcription and beta interferon signaling pathways. J. Virol. 86 (3), 1670–1682. Stack, J., Haga, I.R., Schröder, M., Bartlett, N.W., Maloney, G., Reading, P.C., Fitzgerald, K.A., Smith, G.L., Bowie, A.G., 2005. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J. Exp. Med. 201 (6), 1007–1018. Sullivan, C.S., Ganem, D., 2005. MicroRNAs and viral infection. Mol. Cell 20 (1), 3–7. Suzuki, T., Franchi, L., Toma, C., Ashida, H., Ogawa, M., Yoshikawa, Y., Mimuro, H., ˜ G., 2007. Differential regulation of caspaseInohara, N., Sasakawa, C., Nunez, 1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3 (8), e111. Swaminathan, G., Rossi, F., Sierra, L.J., Gupta, A., Navas-Martín, S., Martín-García, J., 2012. A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages. PLoS Pathog. 8 (9), e1002937. Taganov, K.D., Boldin, M.P., Chang, K.J., Baltimore, D., 2006. NF-{kappa} B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. U.S.A. 103, 12481–12486. Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T.W., Taniguchi, T., 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434 (7030), 243–249. Takeuchi, O., Akira, S., 2010. Pattern recognition receptors and inflammation. Cell 140, 805–820. Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R.L., Akira, S., 2002. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169 (1), 10–14. Tuddenham, L., Pfeffer, S., 2011. Roles and regulation of microRNAs in cytomegalovirus infection. Biochim. Biophys. Acta 1809 (11–12), 613–622. Vasudevan, S., Tong, Y., Steitz, J.A., 2007. Switching from repression to activation: microRNAs can up-regulate translation. Science 318 (5858), 1931–1934. Wang, P., Hou, J., Lin, L., Wang, C., Liu, X., Li, D., Ma, F., Wang, Z., Cao, X., 2010. Inducible microRNA-155 feedback promotes RIG-I-dependent type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J. Immunol. 185 (10), 6226–6233. Williams, A., Flavell, R.A., Eisenbarth, S.C., 2010. The role of NOD-like receptors in shaping adaptive immunity. Curr. Opin. Immunol. 22 (1), 34–40. Xiao, B., Liu, Z., Li, B.S., Tang, B., Li, W., Guo, G., Shi, Y., Wang, F., Wu, Y., Tong, W.D., Guo, H., Mao, X.H., Zou, Q.M., 2009. Induction of microRNA-155 during Helicobacter pylori infection and its negative regulatory role in the inflammatory response. J. Infect. Dis. 200 (6), 916–925. Yoneyama, M., Fujita, T., 2007. Function of RIG-I-like receptors in antiviral innate immunity. J. Biol. Chem. 282 (21), 15315–15318. Yoneyama, M., Fujita, T., 2009. RNA recognition and signal transduction by RIG-I-like receptors. Immunol. Rev. 227 (1), 54–65.
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A. Zhou et al. / Virus Research 184 (2014) 1–6
Yoneyama, M., Kikuchi, M., Natsukawa, T., Shinobu, N., Imaizumi, T., Miyagishi, M., Taira, K., Akira, S., Fujita, T., 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5 (7), 730–737. Yun, J.J., Tsao, M.S., Der, S.D., 2011. Differential utilization of NF-kappaB RELA and RELB in response to extracellular versus intracellular polyIC stimulation in HT1080 cells. BMC Immunol. 12, 15.
Zhang, Q., Xiao, Z., He, F., Zou, J., Wu, S., Liu, Z., 2012. MicroRNAs regulate the pathogenesis of CVB3-induced viral myocarditis. Intervirology (Epub ahead of print). Zhao, Y., Srivastava, D., 2007. A developmental view of microRNA function. Trends Biochem. Sci. 32, 189–197. Zhou, Y., Wang, X., Liu, M., Hu, Q., Song, L., Ye, L., Zhou, D., Ho, W., 2010. A critical function of toll-like receptor-3 in the induction of anti-human immunodeficiency virus activities in macrophages. Immunology 131 (1), 40–49.