Abstract
The innate immune response provides the initial defense against infection. This is accomplished by families of pattern recognition receptors (PRRs) that bind to conserved molecules in bacteria, fungi and viruses. PRRs are finely regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs that are emerging as important regulators in immune responses at the post-transcriptional level, through the inhibition of translation, or by inducing mRNA degradation. It has been shown that miRNAs have unique expression profiles in cells of the innate immune systems and play pivotal roles in regulating the signal pathways of innate receptors, including Toll-like receptors, RIG-I-like receptors and Nod-like receptors. We have summarized the recent literature providing new insights into the regulation of innate receptor pathways by miRNAs.
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Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell, 2010, 140: 805–820
Netea M G, Wijmenga C, O’Neill L A. Genetic variation in Toll-like receptors and disease susceptibility. Nat Immunol, 2012, 13: 535–542
Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol, 2009, 21: 317–337
Loo Y M, Gale M Jr. Immune signaling by RIG-I-like receptors. Immunity, 2011, 34: 680–692
Maekawa T, Kufer T A, Schulze-Lefert P. NLR functions in plant and animal immune systems: so far and yet so close. Nat Immunol, 2011, 12: 817–826
Hancock R E, Nijnik A, Philpott D J. Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol, 2012, 10: 243–254
Qian C, Cao X. Regulation of Toll-like receptor signaling pathways in innate immune responses. Ann N Y Acad Sci, 2012, doi: 10.1111/j1749-6632.2012.06786.x
Han C, Jin J, Xu S, et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol, 2010, 11: 734–742
Rui Y, Liu X, Li N, et al. PECAM-1 ligation negatively regulates TLR4 signaling in macrophages. J Immunol, 2007, 179: 7344–7351
Xu S, Liu X, Bao Y, et al. Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway. Nat Immunol, 2012, 13: 551–559
Liu X, Zhan Z, Li D, et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol, 2011, 12: 416–424
Wang C, Chen T, Zhang J, et al. The E3 ubiquitin ligase Nrdp1 ‘preferentially’ promotes TLR-mediated production of type I interferon. Nat Immunol, 2009, 10: 744–752
Yang M, Wang C, Zhu X, et al. E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKC{zeta}. J Exp Med, 2011, 208: 2099–2112
An H, Hou J, Zhou J, et al. Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat Immunol, 2008, 9: 542–550
An H, Zhao W, Hou J, et al. SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity, 2006, 25: 919–928
An H, Xu H, Zhang M, et al. Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism. Blood, 2005, 105: 4685–4692
Xu H, An H, Hou J, et al. Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Mol Immunol, 2008, 45: 3545–3552
Liu X, Yao M, Li N, et al. CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages. Blood, 2008, 112: 4961–4970
Yao M, Liu X, Li D, et al. Late endosome/lysosome-localized Rab7b suppresses TLR9-initiated proinflammatory cytokine and type I IFN production in macrophages. J Immunol, 2009, 183: 1751–1758
Wang Y, Chen T, Han C, et al. Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. Blood, 2007, 110: 962–971
Wu Y, Zhu X, Li N, et al. CMRF-35-like molecule 3 preferentially promotes TLR9-triggered proinflammatory cytokine production in macrophages by enhancing TNF receptor-associated factor 6 ubiquitination. J Immunol, 2011, 187: 4881–4889
Yang P, An H, Liu X, et al. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a betacatenin-dependent pathway. Nat Immunol, 2010, 11: 487–494
Chen T, Guo J, Han C, et al. Heat shock protein 70, released from heat-stressed tumor cells, initiates antitumor immunity by inducing tumor cell chemokine production and activating dendritic cells via TLR4 pathway. J Immunol, 2009, 182: 1449–1459
Fang H, Wu Y, Huang X, et al. Toll-like receptor 4 (TLR4) is essential for Hsp70-like protein 1 (HSP70L1) to activate dendritic cells and induce Th1 response. J Biol Chem, 2011, 286: 30393–30400
Jiang Y, Chen G, Zhang Y, et al. Nerve growth factor promotes TLR4 signaling-induced maturation of human dendritic cells in vitro through inducible p75NTR 1. J Immunol, 2007, 179: 6297–6304
Ramos H J, Gale M Jr. RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity. Curr Opin Virol, 2011, 1: 167–176
Bonardi V, Cherkis K, Nishimura M T, et al. A new eye on NLR proteins: focused on clarity or diffused by complexity? Curr Opin Immunol, 2012, 24: 41–50
Ebert M S, Sharp P A. Roles for microRNAs in conferring robustness to biological processes. Cell, 2012, 149: 515–524
Yang C, Wei W. The miRNA expression profile of the uveal melanoma. Sci China Life Sci, 2011, 54: 351–358
Mendell J T, Olson E N. MicroRNAs in stress signaling and human disease. Cell, 2012, 148: 1172–1187
Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol, 2010, 11: 373–384
O’Neill L A, Sheedy F J, McCoy C E. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol, 2011, 11: 163–175
Taganov K D, Boldin M P, Chang K J, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA, 2006, 103: 12481–12486
Ceppi M, Pereira P M, Dunand-Sauthier I, et al. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci USA, 2009, 106: 2735–2740
Tili E, Michaille J J, Cimino A, et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol, 2007, 179: 5082–5089
Starczynowski D T, Kuchenbauer F, Argiropoulos B, et al. Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nat Med, 2010, 16: 49–58
Alsaleh G, Suffert G, Semaan N, et al. Bruton’s tyrosine kinase is involved in miR-346-related regulation of IL-18 release by lipopolysaccharide-activated rheumatoid fibroblast-like synoviocytes. J Immunol, 2009, 182: 5088–5097
Li T, Morgan M J, Choksi S, et al. MicroRNAs modulate the noncanonical transcription factor NF-kappaB pathway by regulating expression of the kinase IKKalpha during macrophage differentiation. Nat Immunol, 2010, 11: 799–805
Chen R, Alvero A B, Silasi D A, et al. Regulation of IKKbeta by miR-199a affects NF-kappaB activity in ovarian cancer cells. Oncogene, 2008, 27: 4712–4723
Feng W, Feng Y. MicroRNAs in neural cell development and brain diseases. Sci China Life Sci, 2011, 54: 1103–1112
Li S, Yu B, Wang Y, et al. Identification and functional annotation of novel microRNAs in the proximal sciatic nerve after sciatic nerve transection. Sci China Life Sci, 2011, 54: 806–812
Lehmann S M, Krüger C, Park B, et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci, 2012, 15: 827–835
Chen K, Rajewsky N. The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet, 2007, 8: 93–103
Bazzoni F, Rossato M, Fabbri M, et al. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci USA, 2009, 106: 5282–5287
Qi J, Qiao Y, Wang P, et al. microRNA-210 negatively regulates LPS-induced production of proinflammatory cytokines by targeting NF-kappaB1 in murine macrophages. FEBS Lett, 2012, 586: 1201–1207
Hu X, Chen J, Wang L, et al. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol, 2007, 82: 237–243
Zhang M, Liu Q, Mi S, et al. Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J Immunol, 2011, 186: 4716–4724
Jennewein C, von Knethen A, Schmid T, et al. MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA destabilization. J Biol Chem, 2010, 285: 11846–11853
Lagos D, Pollara G, Henderson S, et al. miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nat Cell Biol, 2010, 12: 513–519
Worm J, Stenvang J, Petri A, et al. Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF. Nucleic Acids Res, 2009, 37: 5784–5792
Sheedy F J, Palsson-McDermott E, Hennessy E J, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol, 2010, 11: 141–147
Iliopoulos D, Jaeger S A, Hirsch H A, et al. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell, 2010, 39: 493–506
Bai Y, Qian C, Qian L, et al. Integrin CD11b negatively regulates TLR9-triggered dendritic cell cross-priming by upregulating microRNA-146a. J Immunol, 2012, 188: 5293–5302
O’Connell R M, Chaudhuri A A, Rao D S, et al. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA, 2009, 106: 7113–7118
Qian C, Jiang X, An H, et al. TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation. Blood, 2006, 108: 2307–2315
Qian C, An H, Yu Y, et al. TLR agonists induce regulatory dendritic cells to recruit Th1 cells via preferential IP-10 secretion and inhibit Th1 proliferation. Blood, 2007, 109: 3308–3315
Semaan N, Frenzel L, Alsaleh G, et al. miR-346 controls release of TNF-alpha protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization. PLoS One, 2011, 6: 1–11
El G M, McCall C E. MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. J Biol Chem, 2010, 285: 20940–20951
Lu T X, Munitz A, Rothenberg M E. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J Immunol, 2009, 182: 4994–5002
Ma F, Liu X, Li D, et al. MicroRNA-466l upregulates IL-10 expression in TLR-triggered macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation. J Immunol, 2010, 184: 6053–6059
Ma F, Xu S, Liu X, et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma. Nat Immunol, 2011, 12: 861–869
Hou J, Wang P, Lin L, et al. MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol, 2009, 183: 2150–2158
Huang Z, Chen X, Yu B, et al. Cloning and functional characterization of rat stimulator of interferon genes (STING) regulated by miR-24. Dev Comp Immunol, 2012, 37: 414–420
MacMicking J D. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat Rev Immunol, 2012, 12: 367–382
Li Y, Fan X, He X, et al. MicroRNA-466l inhibits antiviral innate immune response by targeting interferon-alpha. Cell Mol Immunol, 2012, doi: 10.1038/cmi.2012.35
Li S J, Chen Z, Zhu H H. Influence of miR-122 on IFN-alpha treatment for HCV infection. Zhejiang Da Xue Xue Bao Yi Xue Ban, 2011, 40: 588–592
Papadopoulou A S, Dooley J, Linterman M A, et al. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-alpha receptor. Nat Immunol, 2012, 13: 181–187
Wang P, Gu Y, Zhang Q, et al. Identification of resting and type I IFN-activated human NK cell miRNomes reveals microRNA-378 and microRNA-30e as negative regulators of NK cell cytotoxicity. J Immunol, 2012, 189: 211–221
Umbach J L, Kramer M F, Jurak I, et al. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature, 2008, 454: 780–783
Liang D, Gao Y, Lin X, et al. A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKɛ. Cell Res, 2011, 21: 793–806
Franchi L, Munoz-Planillo R, Nunez G. Sensing and reacting to microbes through the inflammasomes. Nat Immunol, 2012, 13: 325–332
Haneklaus M, Gerlic M, Kurowska-Stolarska M, et al. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1beta production. J Immunol, 2012, 189: 3795–3799
Bauernfeind F, Rieger A, Schildberg F A, et al. NLRP3 inflammasome activity is negatively controlled by miR-223. J Immunol, 2012, 189: 4175–4181
O’Connell R M, Rao D S, Baltimore D. microRNA regulation of inflammatory responses. Annu Rev Immunol, 2012, 30: 295–312
Feng Y, Yu X. Cardinal roles of miRNA in cardiac development and disease. Sci China Life Sci, 2011, 54: 1113–1120
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Zhang, Y., Li, Y. Regulation of innate receptor pathways by microRNAs. Sci. China Life Sci. 56, 13–18 (2013). https://doi.org/10.1007/s11427-012-4428-2
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DOI: https://doi.org/10.1007/s11427-012-4428-2