Key Points
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Multiple microRNAs (miRNAs) are induced by Toll-like receptor (TLR) signalling and regulate the expression of TLR signalling components and TLR-induced cytokines.
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TLR-induced miRNAs can influence the innate inflammatory response and have a role in priming of the adaptive immune system.
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Notable examples of TLR-induced miRNAs are miR-146a, which targets IL-1R-associated kinase 1 (IRAK1) and TNFR-associated factor 6 (TRAF6); miR-155, which targets the negative regulator Src homology 2 (SH2) domain-containing inositol-5′-phosphatase 1 (SHIP1); and miR-21, which targets the interleukin-10 (IL-10) suppressor molecule programmed cell death 4 (PDCD4).
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miRNAs function as fine-tuners of the inflammatory response and have a role in the resolution of inflammation.
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Part of the anti-inflammatory effect of IL-10 might be a result of the selective inhibition of miR-155 induced by TLR signalling.
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Aberrant expression of TLR-specific miRNAs is associated with inflammatory diseases such as rheumatoid arthritis.
Abstract
Toll-like receptor (TLR) signalling must be tightly regulated to avoid excessive inflammation and to allow for tissue repair and the return to homeostasis after infection and tissue injury. MicroRNAs (miRNAs) have emerged as important controllers of TLR signalling. Several miRNAs are induced by TLR activation in innate immune cells and these and other miRNAs target the 3′ untranslated regions of mRNAs encoding components of the TLR signalling system. miRNAs are also proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of inflammatory diseases.
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References
O'Neill, L. A. How Toll-like receptors signal: what we know and what we don't know. Curr. Opin. Immunol. 18, 3–9 (2006).
Cook, D. N., Pisetsky, D. S. & Schwartz, D. A. Toll-like receptors in the pathogenesis of human disease. Nature Immunol. 5, 975–979 (2004).
Liew, F. Y., Xu, D., Brint, E. K. & O'Neill, L. A. Negative regulation of Toll-like receptor-mediated immune responses. Nature Rev. Immunol. 5, 446–458 (2005).
Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010). An in-depth study showing that miRNAs function at the post-transcriptional level mainly by decreasing mRNA levels rather than by inhibiting translation.
Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).
Carpenter, S. & O'Neill, L. A. Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins. Biochem. J. 422, 1–10 (2009).
Cai, X., Hagedorn, C. H. & Cullen, B. R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10, 1957–1966 (2004).
Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).
Ruggiero, T. et al. LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages. FASEB J. 23, 2898–2908 (2009).
McCoy, C. E. et al. IL-10 inhibits miR-155 induction by Toll-like receptors. J. Biol. Chem. 285, 20492–20498 (2010). This is the first demonstration of modulation of a TLR-induced miRNA (miR-155) by IL-10, an effect that might be important for the anti-inflammatory functions of IL-10.
Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A. & Bazan, J. F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl Acad. Sci. USA 95, 588–593 (1998).
Muzio, M. et al. Differential expression and regulation of Toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J. Immunol. 164, 5998–6004 (2000).
Hornung, V. et al. Quantitative expression of Toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J. Immunol. 168, 4531–4537 (2002).
Zarember, K. A. & Godowski, P. J. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products and cytokines. J. Immunol. 168, 554–561 (2002).
Jarrossay, D., Napolitani, G., Colonna, M., Sallusto, F. & Lanzavecchia, A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur. J. Immunol. 31, 3388–3393 (2001).
Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).
Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004). The first study to investigate the specific role of miRNAs in haematopoiesis and lineage differentiation.
Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).
Palsson-McDermott, E. M. et al. TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway. Nature Immunol. 10, 579–586 (2009).
Heikham, R. & Shankar, R. Flanking region sequence information to refine microRNA target predictions. J. Biosci. 35, 105–118 (2010).
Johnnidis, J. B. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008). This study reports an important role for miR-223 in the regulation of granulocytes and macrophages.
Androulidaki, A. et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31, 220–231 (2009).
Chen, X. M., Splinter, P. L., O'Hara, S. P. & LaRusso, N. F. A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J. Biol. Chem. 282, 28929–28938 (2007).
Benakanakere, M. R. et al. Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J. Biol. Chem. 284, 23107–23115 (2009).
Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA 103, 12481–12486 (2006). The first study to profile the miRNAs that are induced by TLR signalling and to propose that miRNAs function as negative regulators by targeting key proteins in the TLR signalling pathways.
Hou, J. et al. MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J. Immunol. 183, 2150–2158 (2009).
Ceppi, M. et al. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc. Natl Acad. Sci. USA 106, 2735–2740 (2009).
Tang, B. et al. Identification of MyD88 as a novel target of miR-155, involved in negative regulation of Helicobacter pylori-induced inflammation. FEBS Lett. 584, 1481–1486 (2010).
Huang, R. S., Hu, G. Q., Lin, B., Lin, Z. Y. & Sun, C. C. MicroRNA-155 silencing enhances inflammatory response and lipid uptake in oxidized low-density lipoprotein-stimulated human THP-1 macrophages. J. Investig. Med. 51, 961–967 (2010).
Starczynowski, D. T. et al. Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nature Med. 16, 49–58 (2010). The first study to show directly that chromosomal deletion of miRNAs can be associated with a particular disease: in this case, 5q myelodysplastic syndrome.
Mansell, A. et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nature Immunol. 7, 148–155 (2006).
Alsaleh, G. 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. 182, 5088–5097 (2009).
Chen, K. & Rajewsky, N. The evolution of gene regulation by transcription factors and microRNAs. Nature Rev. Genet. 8, 93–103 (2007).
Martinez, N. J. & Walhout, A. J. The interplay between transcription factors and microRNAs in genome-scale regulatory networks. Bioessays 31, 435–445 (2009).
Kohlhaas, S. et al. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J. Immunol. 182, 2578–2582 (2009).
Iliopoulos, D., Jaeger, S. A., Hirsch, H. A., Bulyk, M. L. & Struhl, K. 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 39, 493–506 (2010).
Li, T. et al. MicroRNAs modulate the noncanonical transcription factor NF-κB pathway by regulating expression of the kinase IKKα during macrophage differentiation. Nature Immunol. 11, 799–805 (2010).
Chen, R. et al. Regulation of IKKβ by miR-199a affects NF-κB activity in ovarian cancer cells. Oncogene 27, 4712–4723 (2008).
Gottwein, E. et al. A viral microRNA functions as an orthologue of cellular miR-155. Nature 450, 1096–1099 (2007). One of the first studies to show that certain viral miRNAs are homologous to cellular miRNAs, providing another mechanism by which viruses can manipulate the host immune response.
Xiao, B. et al. Induction of microRNA-155 during Helicobacter pylori infection and its negative regulatory role in the inflammatory response. J. Infect. Dis. 200, 916–925 (2009).
Bazzoni, F. et al. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc. Natl Acad. Sci. USA 106, 5282–5287 (2009).
Worm, J. et al. Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebpβ and down-regulation of G-CSF. Nucleic Acids Res. 37, 5784–5792 (2009).
Costinean, S. et al. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein-β are targeted by miR-155 in B cells of Eμ-MiR-155 transgenic mice. Blood 114, 1374–1382 (2009).
Jennewein, C., von Knethen, A., Schmid, T. & Brune, B. MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor-γ (PPARγ) mRNA destabilization. J. Biol. Chem. 285, 11846–11853 (2010).
Lagos, D. et al. miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nature Cell Biol. 12, 513–519 (2010).
Asirvatham, A. J., Gregorie, C. J., Hu, Z., Magner, W. J. & Tomasi, T. B. MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. Mol. Immunol. 45, 1995–2006 (2008).
Asirvatham, A. J., Magner, W. J. & Tomasi, T. B. miRNA regulation of cytokine genes. Cytokine 45, 58–69 (2009).
Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).
Viswanathan, S. R., Daley, G. Q. & Gregory, R. I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).
Tili, E. et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-α stimulation and their possible roles in regulating the response to endotoxin shock. J. Immunol. 179, 5082–5089 (2007).
Sharma, A. et al. Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc. Natl Acad. Sci. USA 106, 5761–5766 (2009).
Lu, T. X., Munitz, A. & Rothenberg, M. E. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J. Immunol. 182, 4994–5002 (2009).
Carballo, E., Lai, W. S. & Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin. Science 281, 1001–1005 (1998).
Lai, W. S. et al. Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor-α mRNA. Mol. Cell Biol. 19, 4311–4323 (1999).
Stoecklin, G. et al. Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. J. Biol. Chem. 283, 11689–11699 (2008).
Jing, Q. et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623–634 (2005).
El Gazzar, M. & McCall, C. E. MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. J. Biol. Chem. 285, 20940–20951 (2010).
Ma, F. 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. 184, 6053–6059 (2010).
Vasudevan, S. & Steitz, J. A. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128, 1105–1118 (2007).
Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).
Shaked, I. et al. MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity 31, 965–973 (2009).
Sheedy, F. J. et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nature Immunol. 11, 141–147 (2010).
Yang, H. S. et al. The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Mol. Cell Biol. 23, 26–37 (2003).
Loh, P. G. et al. Structural basis for translational inhibition by the tumour suppressor Pdcd4. EMBO J. 28, 274–285 (2009).
Koromilas, A. E., Lazaris-Karatzas, A. & Sonenberg, N. mRNAs containing extensive secondary structure in their 5′ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J. 11, 4153–4158 (1992).
O'Connell, R. M., Chaudhuri, A. A., Rao, D. S. & Baltimore, D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl Acad. Sci. USA 106, 7113–7118 (2009). This paper identifies SHIP1 as an important target of miR-155 in TLR signalling.
Cremer, T. J. et al. MiR-155 induction by F. novicida but not the virulent F. tularensis results in SHIP down-regulation and enhanced pro-inflammatory cytokine response. PLoS One 4, e8508 (2009).
An, H. 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 105, 4685–4692 (2005).
Gabhann, J. N. et al. Absence of SHIP-1 results in constitutive phosphorylation of tank-binding kinase 1 and enhanced TLR3-dependent IFN-β production. J. Immunol. 184, 2314–2320 (2010).
Sly, L. M., Rauh, M. J., Kalesnikoff, J., Buchse, T. & Krystal, G. SHIP, SHIP2 and PTEN activities are regulated in vivo by modulation of their protein levels: SHIP is up-regulated in macrophages and mast cells by lipopolysaccharide. Exp. Hematol. 31, 1170–1181 (2003).
Perry, M. M. et al. Rapid changes in microRNA-146a expression negatively regulate the IL-1β-induced inflammatory response in human lung alveolar epithelial cells. J. Immunol. 180, 5689–5698 (2008).
Bhaumik, D. et al. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging 1, 402–411 (2009).
Jones, S. W. et al. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-α and MMP13. Osteoarthritis Cartilage 17, 464–472 (2009).
Nahid, M. A., Pauley, K. M., Satoh, M. & Chan, E. K. miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity. J. Biol. Chem. 284, 34590–34599 (2009).
Curtale, G. et al. An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood 115, 265–273 (2010).
Cameron, J. E. et al. Epstein–Barr virus latent membrane protein 1 induces cellular microRNA miR-146a, a modulator of lymphocyte signaling pathways. J. Virol. 82, 1946–1958 (2008).
Motsch, N., Pfuhl, T., Mrazek, J., Barth, S. & Grasser, F. A. Epstein–Barr virus-encoded latent membrane protein 1 (LMP1) induces the expression of the cellular microRNA miR-146a. RNA Biol. 4, 131–137 (2007).
Chassin, C. et al. miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 8, 358–368 (2010).
Jurkin, J. et al. miR-146a is differentially expressed by myeloid dendritic cell subsets and desensitizes cells to TLR2-dependent activation. J. Immunol. 184, 4955–4965 (2010).
Liu, G. et al. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc. Natl Acad. Sci. USA 106, 15819–15824 (2009).
Stanczyk, J. et al. Altered expression of microRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 58, 1001–1009 (2008). One of the first studies to analyse miRNAs in the context of rheumatoid arthritis.
Wang, P. et al. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J. Immunol. 185, 6226–6233 (2010).
O'Connell, R. M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).
Zhou, H. et al. miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells. Blood 116, 5885–5894 (2010).
Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nature Rev. Immunol. 7, 454–465 (2007).
McCoy, C. E. The role of miRNAs in cytokine signalling. Front. Biosci. (in the press).
Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007). The first study to analyse a role for miR-155 in the immune system using miR-155-deficient mice.
Vigorito, E. et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27, 847–859 (2007).
Martinez-Nunez, R. T., Louafi, F., Friedmann, P. S. & Sanchez-Elsner, T. MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J. Biol. Chem. 284, 16334–16342 (2009).
Marta, M., Andersson, A., Isaksson, M., Kampe, O. & Lobell, A. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur. J. Immunol. 38, 565–575 (2008).
Dorsett, Y. et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity 28, 630–638 (2008).
Teng, G. et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28, 621–629 (2008). Through genetic mutation of the miRNA binding site, references 91 and 92 describe the direct effect of miR-155 on one of its target mRNAs.
Asadullah, K., Sterry, W. & Volk, H. D. Interleukin-10 therapy — review of a new approach. Pharmacol. Rev. 55, 241–269 (2003).
O'Garra, A., Barrat, F. J., Castro, A. G., Vicari, A. & Hawrylowicz, C. Strategies for use of IL-10 or its antagonists in human disease. Immunol. Rev. 223, 114–131 (2008).
Hunter, M. P. et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One 3, e3694 (2008).
Luo, S. S. et al. Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol. Reprod. 81, 717–729 (2009).
Michael, A. et al. Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis. 16, 34–38 (2010).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biol. 9, 654–659 (2007). An important paper showing that miRNAs in exosomes can mediate effects on neighbouring cells in an autocrine manner.
Camussi, G., Deregibus, M. C., Bruno, S., Cantaluppi, V. & Biancone, L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 78, 838–848 (2010).
van Niel, G., Porto-Carreiro, I., Simoes, S. & Raposo, G. Exosomes: a common pathway for a specialized function. J. Biochem. 140, 13–21 (2006).
Matsumoto, K. et al. Exosomes secreted from monocyte-derived dendritic cells support in vitro naive CD4+ T cell survival through NF-κB activation. Cell. Immunol. 231, 20–29 (2004).
Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).
Thery, C. et al. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nature Immunol. 3, 1156–1162 (2002).
Recchiuti, A., Krishnamoorthy, S., Fredman, G., Chiang, N. & Serhan, C. N. MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1–miRNA circuits. FASEB J. 18 Oct 2010 (doi:10.1096/fj.10-169599).
Wu, F. et al. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2α. Gastroenterology 135, 1624–1635 (2008).
Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006).
Chen, R., Alvero, A. B., Silasi, D. A., Steffensen, K. D. & Mor, G. Cancers take their Toll — the function and regulation of Toll-like receptors in cancer cells. Oncogene 27, 225–233 (2008).
Hussain, S. P. & Harris, C. C. Inflammation and cancer: an ancient link with novel potentials. Int. J. Cancer 121, 2373–2380 (2007).
Kanwar, J. R., Mahidhara, G. & Kanwar, R. K. MicroRNA in human cancer and chronic inflammatory diseases. Front. Biosci. 2, 1113–1126 (2010).
Pauley, K. M., Cha, S. & Chan, E. K. MicroRNA in autoimmunity and autoimmune diseases. J. Autoimmun. 32, 189–194 (2009).
Oglesby, I. K., McElvaney, N. G. & Greene, C. M. MicroRNAs in inflammatory lung disease — master regulators or target practice? Respir. Res. 11, 148 (2010).
Fasseu, M. et al. Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease. PLoS One 5, e13160 (2010).
Iborra, M., Bernuzzi, F., Invernizzi, P. & Danese, S. MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun. Rev. 11 Jul 2010 (doi:10.1016/j.autrev.2010.07.002).
Wu, F. et al. Identification of microRNAs associated with ileal and colonic Crohn's disease. Inflamm. Bowel Dis. 16, 1729–1738 (2010).
Nakasa, T. et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 58, 1284–1292 (2008).
Murata, K. et al. Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res. Ther. 12, R86 (2010).
Stanczyk, J. et al. Altered expression of miR-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 27 Oct 2010 (doi:10.1002/art.30115).
Iliopoulos, D., Malizos, K. N., Oikonomou, P. & Tsezou, A. Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS ONE 3, e3740 (2008).
Sonkoly, E. et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS ONE 2, e610 (2007).
Dai, Y. et al. Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 16, 939–946 (2007).
Chatzikyriakidou, A., Voulgari, P. V., Georgiou, I. & Drosos, A. A. A polymorphism in the 3′-UTR of interleukin-1 receptor-associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility. Joint Bone Spine 77, 411–413 (2010).
Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008). This paper shows that each miRNA can repress the production of proteins on a global scale, although this repression is relatively mild.
Kuchen, S. et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 32, 828–839 (2010).
Brown, B. D. et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nature Biotechnol. 25, 1457–1467 (2007).
O'Connell, R. M., Taganov, K. D., Boldin, M. P., Cheng, G. & Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl Acad. Sci. USA 104, 1604–1609 (2007).
Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007). This study provides an in-depth analysis of miRNA libraries from multiple organs and cell types.
Yin, Q. et al. MicroRNA-155 is an Epstein–Barr virus-induced gene that modulates Epstein–Barr virus-regulated gene expression pathways. J. Virol. 82, 5295–5306 (2008).
Moschos, S. A. et al. Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids. BMC Genomics 8, 240 (2007).
Gantier, M. P. New perspectives in microRNA regulation of innate immunity. J. Interferon Cytokine Res. 30, 283–289 (2010).
Zhou, R., Hu, G., Gong, A. Y. & Chen, X. M. Binding of NF-κB p65 subunit to the promoter elements is involved in LPS-induced transactivation of miRNA genes in human biliary epithelial cells. Nucleic Acids Res. 38, 3222–3232 (2010).
Zhou, R. et al. NF-κB p65-dependent transactivation of miRNA genes following Cryptosporidium parvum infection stimulates epithelial cell immune responses. PLoS Pathog. 5, e1000681 (2009).
Cameron, J. E. et al. Epstein–Barr virus growth/latency III program alters cellular microRNA expression. Virology 382, 257–266 (2008).
O'Hara, S. P. et al. NFκB p50-CCAAT/enhancer-binding protein-β (C/EBPβ)-mediated transcriptional repression of microRNA let-7i following microbial infection. J. Biol. Chem. 285, 216–225 (2010).
Hu, G. et al. MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge. J. Immunol. 183, 1617–1624 (2009).
Acknowledgements
The authors would like to thank their respective funding bodies: L.A.O'N. is supported by Science Foundation Ireland, F.J.S. was supported by the Irish Research Council for Science, Engineering & Technology and C.E.M. is supported by a Health Research Board Ireland/Marie Curie fellowship.
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Glossary
- Toll-like receptors
-
(TLRs). A family of pattern recognition receptors that detect conserved microbial components during infection and initiate an inflammatory response. They are commonly expressed by cells of the immune system including macrophages and dendritic cells, as well as other sentinel cells such as epithelial cells. TLRs have also been implicated in the recognition of endogenous danger signals that are present in the body during disease.
- MicroRNAs
-
(miRNAs). Small (18–22 nucleotide) RNA molecules that regulate gene expression by binding to the 3′ untranslated regions of specific mRNAs. They are derived from larger precursor and primary transcript molecules and are themselves transcriptionally regulated in a manner similar to mRNAs.
- Nuclear factor-κB
-
(NF-κB). A highly pro-inflammatory transcription factor that is activated by many stimuli, including TLR activation. NF-κB complexes are held inactive in the cytoplasm by inhibitor of NF-κB (IκB) proteins. Degradation and removal of IκB is a common NF-κB-activating process and TLR signalling pathways converge on this mechanism. NF-κB-responsive genes include those encoding cytokines, chemokines and antimicrobial enzymes.
- 3′ untranslated region
-
(3′ UTR). The RNA sequence found 3′ (downstream) of the stop codon in the open reading frame of a mRNA before the poly(A) tail sequence. 3′ UTR sequences vary in length and nucleotide content. It is now recognized that 3′ UTR sequences contain regulatory RNA sequences that determine the translation efficiency and stability of the mRNA, including miRNA target sites.
- Foam cells
-
Macrophages that localize at sites of early vascular inflammation and that subsequently ingest oxidized low-density lipoprotein and slowly become overloaded with lipids. Foam cells eventually die and attract more macrophages, further propagating inflammation in blood vessels.
- LPS tolerance
-
A transient state of hyporesponsiveness to subsequent stimulation with lipopolysaccharide (LPS) after TLR activation.
- Cholinergic anti-inflammatory pathway
-
This pathway fine-tunes cytokine production during inflammation in a highly regulated and reflexive manner. Interaction of acetylcholine with the α7-nicotinic acetylcholine receptor expressed by macrophages results in the suppression of pro-inflammatory cytokine production. The main component of this pathway is the vagus nerve of the parasympathetic branch of the autonomic nervous system.
- Luciferase reporter assay
-
A method to measure the transcriptional response. This assay uses a regulatory sequence from a gene of interest fused to the gene that encodes luciferase to determine the effect of the regulatory sequence on gene expression. It is commonly used to determine promoter sequences and transcription factor-binding sites, but can also be used to determine miRNA targeting through the fusion of a 3′ UTR sequence containing miRNA target sites to the luciferase gene.
- Morpholino-modified oligonucleotide
-
A nucleic acid analogue in which the base and phosphate linkages structurally differ from regular DNA or RNA. They are commonly 25 nucleotides in length and they function by blocking access of RNA-binding proteins or RNAs to target sites in mRNAs to which they are antisense. They can be used to protect a mRNA from miRNA activity by targeting the morpholino-modified oligonucleotide to a miRNA target site in a specific mRNA.
- Langerhans cells
-
Professional antigen-presenting dendritic cells that are localized in the skin epidermis.
- Class switching
-
The somatic recombination process by which immunoglobulin isotypes are switched from IgM to IgG, IgA or IgE.
- Experimental autoimmune encephalomyelitis
-
(EAE). An animal model of human multiple sclerosis. EAE develops in susceptible rodents and primates after immunization with antigens derived from the central nervous system.
- Germinal centre
-
A lymphoid structure that arises within B cell follicles after immunization with, or exposure to, a T cell-dependent antigen. It is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.
- Exosomes
-
Small lipid bilayer vesicles that are released from dendritic cells and other cells. They are composed of cell membranes or are derived from the membranes of intracellular vesicles. They might contain peptide–MHC complexes and directly interact with antigen-specific lymphocytes, or they might be taken up by other antigen-presenting cells.
- Resolvin D1
-
A lipid mediator that is induced in the resolution phase following acute inflammation. Resolvins are synthesized from the essential omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
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O'Neill, L., Sheedy, F. & McCoy, C. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11, 163–175 (2011). https://doi.org/10.1038/nri2957
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DOI: https://doi.org/10.1038/nri2957
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