Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MicroRNAs: the fine-tuners of Toll-like receptor signalling

Key Points

  • Multiple microRNAs (miRNAs) are induced by Toll-like receptor (TLR) signalling and regulate the expression of TLR signalling components and TLR-induced cytokines.

  • TLR-induced miRNAs can influence the innate inflammatory response and have a role in priming of the adaptive immune system.

  • 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).

  • miRNAs function as fine-tuners of the inflammatory response and have a role in the resolution of inflammation.

  • Part of the anti-inflammatory effect of IL-10 might be a result of the selective inhibition of miR-155 induced by TLR signalling.

  • 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: miRNAs function together with other mechanisms to control the expression of TLR signalling components.
Figure 2: miRNA-mediated control of cytokines induced by TLRs and IL-1 signalling.
Figure 3: Fine-tuning of TLR4 signalling by miR-155 and miR-21.
Figure 4: The role of miRNAs in the resolution of inflammation.

Similar content being viewed by others

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Cook, D. N., Pisetsky, D. S. & Schwartz, D. A. Toll-like receptors in the pathogenesis of human disease. Nature Immunol. 5, 975–979 (2004).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Heikham, R. & Shankar, R. Flanking region sequence information to refine microRNA target predictions. J. Biosci. 35, 105–118 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. Androulidaki, A. et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31, 220–231 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Benakanakere, M. R. et al. Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J. Biol. Chem. 284, 23107–23115 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. Chen, K. & Rajewsky, N. The evolution of gene regulation by transcription factors and microRNAs. Nature Rev. Genet. 8, 93–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Martinez, N. J. & Walhout, A. J. The interplay between transcription factors and microRNAs in genome-scale regulatory networks. Bioessays 31, 435–445 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  Google Scholar 

  38. Chen, R. et al. Regulation of IKKβ by miR-199a affects NF-κB activity in ovarian cancer cells. Oncogene 27, 4712–4723 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

  47. Asirvatham, A. J., Magner, W. J. & Tomasi, T. B. miRNA regulation of cytokine genes. Cytokine 45, 58–69 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Viswanathan, S. R., Daley, G. Q. & Gregory, R. I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Sharma, A. et al. Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc. Natl Acad. Sci. USA 106, 5761–5766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. Carballo, E., Lai, W. S. & Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin. Science 281, 1001–1005 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Stoecklin, G. et al. Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. J. Biol. Chem. 283, 11689–11699 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jing, Q. et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623–634 (2005).

    CAS  PubMed  Google Scholar 

  57. El Gazzar, M. & McCall, C. E. MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. J. Biol. Chem. 285, 20940–20951 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. Vasudevan, S. & Steitz, J. A. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell 128, 1105–1118 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Shaked, I. et al. MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity 31, 965–973 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  Google Scholar 

  63. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Loh, P. G. et al. Structural basis for translational inhibition by the tumour suppressor Pdcd4. EMBO J. 28, 274–285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. 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).

    Article  CAS  PubMed  Google Scholar 

  77. 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).

    Article  CAS  PubMed  Google Scholar 

  78. Chassin, C. et al. miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 8, 358–368 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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.

    Article  PubMed  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. O'Connell, R. M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nature Rev. Immunol. 7, 454–465 (2007).

    Article  CAS  Google Scholar 

  86. McCoy, C. E. The role of miRNAs in cytokine signalling. Front. Biosci. (in the press).

  87. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Vigorito, E. et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27, 847–859 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. Dorsett, Y. et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity 28, 630–638 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Asadullah, K., Sterry, W. & Volk, H. D. Interleukin-10 therapy — review of a new approach. Pharmacol. Rev. 55, 241–269 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  Google Scholar 

  95. Hunter, M. P. et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One 3, e3694 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    Article  CAS  PubMed  Google Scholar 

  97. Michael, A. et al. Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis. 16, 34–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. 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.

    Article  CAS  PubMed  Google Scholar 

  99. 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).

    Article  CAS  PubMed  Google Scholar 

  100. van Niel, G., Porto-Carreiro, I., Simoes, S. & Raposo, G. Exosomes: a common pathway for a specialized function. J. Biochem. 140, 13–21 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

  102. Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Thery, C. et al. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nature Immunol. 3, 1156–1162 (2002).

    Article  CAS  Google Scholar 

  104. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wu, F. et al. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2α. Gastroenterology 135, 1624–1635 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006).

    Article  CAS  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. Hussain, S. P. & Harris, C. C. Inflammation and cancer: an ancient link with novel potentials. Int. J. Cancer 121, 2373–2380 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Kanwar, J. R., Mahidhara, G. & Kanwar, R. K. MicroRNA in human cancer and chronic inflammatory diseases. Front. Biosci. 2, 1113–1126 (2010).

    Article  Google Scholar 

  110. Pauley, K. M., Cha, S. & Chan, E. K. MicroRNA in autoimmunity and autoimmune diseases. J. Autoimmun. 32, 189–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Oglesby, I. K., McElvaney, N. G. & Greene, C. M. MicroRNAs in inflammatory lung disease — master regulators or target practice? Respir. Res. 11, 148 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. Wu, F. et al. Identification of microRNAs associated with ileal and colonic Crohn's disease. Inflamm. Bowel Dis. 16, 1729–1738 (2010).

    Article  PubMed  Google Scholar 

  115. Nakasa, T. et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 58, 1284–1292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Murata, K. et al. Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res. Ther. 12, R86 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    Article  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sonkoly, E. et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS ONE 2, e610 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dai, Y. et al. Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 16, 939–946 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. 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).

    Article  CAS  PubMed  Google Scholar 

  122. 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.

    Article  CAS  PubMed  Google Scholar 

  123. Kuchen, S. et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 32, 828–839 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    Article  CAS  Google Scholar 

  125. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gantier, M. P. New perspectives in microRNA regulation of innate immunity. J. Interferon Cytokine Res. 30, 283–289 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cameron, J. E. et al. Epstein–Barr virus growth/latency III program alters cellular microRNA expression. Virology 382, 257–266 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. 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).

    Article  CAS  PubMed  Google Scholar 

  134. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luke A. O'Neill.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

TargetScan

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).

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2957

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing