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The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α

Nature Medicine volume 18, pages 1077–1086 (2012)Cite this article

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Abstract

Inflammatory cytokines such as interleukin-17 (IL-17) promote inflammatory autoimmune diseases. Although several microRNAs (miRNAs) have been shown to regulate autoimmune pathogenesis by affecting lymphocyte development and function, the role of miRNAs in resident cells present in inflammatory lesions remains unclear. Here we show that miR-23b is downregulated in inflammatory lesions of humans with lupus or rheumatoid arthritis, as well as in the mouse models of lupus, rheumatoid arthritis or multiple sclerosis. IL-17 downregulates miR-23b expression in human fibroblast-like synoviocytes, mouse primary kidney cells and astrocytes and is essential for the downregulation of miR-23b during autoimmune pathogenesis. In turn, miR-23b suppresses IL-17−, tumor necrosis factor α (TNF-α)− or IL-1β–induced NF-κB activation and inflammatory cytokine expression by targeting TGF-β–activated kinase 1/MAP3K7 binding protein 2 (TAB2), TAB3 and inhibitor of nuclear factor κ-B kinase subunit α (IKK-α) and, consequently, represses autoimmune inflammation. Thus, IL-17 contributes to autoimmune pathogenesis by suppressing miR-23b expression in radio-resident cells and promoting proinflammatory cytokine expression.

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Figure 1: MiR-23b expression is downregulated in inflammatory lesions in autoimmune disease.
Figure 2: IL-17 is responsible for downregulating miR-23b during inflammatory autoimmune pathogenesis.
Figure 3: MiR-23b suppresses the pathogenesis of autoimmune disease in mouse models.
Figure 4: MiR-23b targets TAB2, TAB3 and IKK-α.
Figure 5: MiR-23b inhibits inflammatory cytokine-mediated signaling and gene expression.
Figure 6: TAB2 and TAB3 are functional targets of miR-23b.

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References

  1. Firestein, G.S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    Article  CAS  Google Scholar 

  2. Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008).

    Article  CAS  Google Scholar 

  3. Rahman, A. & Isenberg, D.A. Systemic lupus erythematosus. N. Engl. J. Med. 358, 929–939 (2008).

    Article  CAS  Google Scholar 

  4. Zhu, S. & Qian, Y. IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin. Sci. (Lond.) 122, 487–511 (2012).

    Article  CAS  Google Scholar 

  5. Feldmann, M., Brennan, F.M. & Maini, R.N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  Google Scholar 

  6. Smolen, J.S., Steiner, G. & Aringer, M. Anti-cytokine therapy in systemic lupus erythematosus. Lupus 14, 189–191 (2005).

    Article  CAS  Google Scholar 

  7. Sospedra, M. & Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683–747 (2005).

    Article  CAS  Google Scholar 

  8. Williams, R.O., Paleolog, E. & Feldmann, M. Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases. Curr. Opin. Pharmacol. 7, 412–417 (2007).

    Article  CAS  Google Scholar 

  9. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010).

    Article  Google Scholar 

  10. Lipsky, P.E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N. Engl. J. Med. 343, 1594–1602 (2000).

    Article  CAS  Google Scholar 

  11. Geyer, M. & Muller-Ladner, U. Actual status of antiinterleukin-1 therapies in rheumatic diseases. Curr. Opin. Rheumatol. 22, 246–251 (2010).

    Article  CAS  Google Scholar 

  12. Genovese, M.C. et al. LY2439821, a humanized anti–interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum. 62, 929–939 (2010).

    Article  CAS  Google Scholar 

  13. Lu, L.F. et al. Function of miR-146a in controlling Treg cell–mediated regulation of Th1 responses. Cell 142, 914–929 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Du, C. et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 10, 1252–1259 (2009).

    Article  CAS  Google Scholar 

  16. Stittrich, A.B. et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat. Immunol. 11, 1057–1062 (2010).

    Article  CAS  Google Scholar 

  17. Xiao, C. et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131, 146–159 (2007).

    Article  CAS  Google Scholar 

  18. Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Johnnidis, J.B. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008).

    Article  CAS  Google Scholar 

  21. Lu, L.F. et al. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30, 80–91 (2009).

    Article  CAS  Google Scholar 

  22. Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17–92 expression in lymphocytes. Nat. Immunol. 9, 405–414 (2008).

    Article  CAS  Google Scholar 

  23. Ponomarev, E.D., Veremeyko, T., Barteneva, N., Krichevsky, A.M. & Weiner, H.L. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat. Med. 17, 64–70 (2011).

    Article  CAS  Google Scholar 

  24. O'Connell, R.M., Rao, D.S., Chaudhuri, A.A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nat. Rev. Immunol. 10, 111–122 (2010).

    Article  CAS  Google Scholar 

  25. Nakamachi, Y. et al. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 60, 1294–1304 (2009).

    Article  Google Scholar 

  26. Junker, A. et al. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132, 3342–3352 (2009).

    Article  Google Scholar 

  27. Dai, Y. et al. Comprehensive analysis of microRNA expression patterns in renal biopsies of lupus nephritis patients. Rheumatol. Int. 29, 749–754 (2009).

    Article  CAS  Google Scholar 

  28. Pan, W. et al. MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J. Immunol. 184, 6773–6781 (2010).

    Article  CAS  Google Scholar 

  29. Li, J. et al. Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res. Ther. 12, R81 (2010).

    Article  Google Scholar 

  30. De Santis, G. et al. Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J. Neuroimmunol. 226, 165–171 (2010).

    Article  CAS  Google Scholar 

  31. 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  Google Scholar 

  32. 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).

    Article  CAS  Google Scholar 

  33. Chang, S.H., Park, H. & Dong, C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J. Biol. Chem. 281, 35603–35607 (2006).

    Article  CAS  Google Scholar 

  34. Sønder, S.U. et al. IL-17-induced NF-κB activation via CIKS/Act1: physiologic significance and signaling mechanisms. J. Biol. Chem. 286, 12881–12890 (2011).

    Article  Google Scholar 

  35. Qian, Y. et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol. 8, 247–256 (2007).

    Article  CAS  Google Scholar 

  36. Ma, F. et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nat. Immunol. 12, 861–869 (2011).

    Article  CAS  Google Scholar 

  37. Rodriguez, A., Griffiths-Jones, S., Ashurst, J.L. & Bradley, A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 14, 1902–1910 (2004).

    Article  CAS  Google Scholar 

  38. Yamamoto, M. et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein I(Bζ. Nature 430, 218–222 (2004).

    Article  CAS  Google Scholar 

  39. Shen, F., Ruddy, M.J., Plamondon, P. & Gaffen, S.L. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17– and TNF-α–induced genes in bone cells. J. Leukoc. Biol. 77, 388–399 (2005).

    Article  CAS  Google Scholar 

  40. Kao, C.Y., Kim, C., Huang, F. & Wu, R. Requirements for two proximal NF-κB binding sites and IκB-ζ in IL-17A–induced human β-defensin 2 expression by conducting airway epithelium. J. Biol. Chem. 283, 15309–15318 (2008).

    Article  CAS  Google Scholar 

  41. Rossi, R.L. et al. Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b. Nat. Immunol. 12, 796–803 (2011).

    Article  CAS  Google Scholar 

  42. Ishitani, T. et al. Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J. 22, 6277–6288 (2003).

    Article  CAS  Google Scholar 

  43. Qian, Y., Kang, Z., Liu, C. & Li, X. IL-17 signaling in host defense and inflammatory diseases. Cell. Mol. Immunol. 7, 328–333 (2010).

    Article  CAS  Google Scholar 

  44. Onishi, R.M. & Gaffen, S.L. Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology 129, 311–321 (2010).

    Article  CAS  Google Scholar 

  45. Iwakura, Y., Ishigame, H., Saijo, S. & Nakae, S. Functional specialization of interleukin-17 family members. Immunity 34, 149–162 (2011).

    Article  CAS  Google Scholar 

  46. Hartupee, J. et al. IL-17 signaling for mRNA stabilization does not require TNF receptor–associated factor 6. J. Immunol. 182, 1660–1666 (2009).

    Article  CAS  Google Scholar 

  47. Bulek, K. et al. The inducible kinase IKKi is required for IL-17–dependent signaling associated with neutrophilia and pulmonary inflammation. Nat. Immunol. 12, 844–852 (2011).

    Article  CAS  Google Scholar 

  48. Sun, D. et al. Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nat. Immunol. 12, 853–860 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  50. Zhang, H. et al. Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis. Nat. Commun. 2, 554 (2011).

    Article  Google Scholar 

  51. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009).

    Article  CAS  Google Scholar 

  52. Zhu, S. et al. Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling. J. Exp. Med. 207, 2647–2662 (2010).

    Article  CAS  Google Scholar 

  53. Kanayama, A. et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Mol. Cell 15, 535–548 (2004).

    Article  CAS  Google Scholar 

  54. Liu, C. et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci. Signal. 2, ra63 (2009).

    Google Scholar 

  55. Shen, F. et al. IL-17 receptor signaling inhibits C/EBPβ by sequential phosphorylation of the regulatory 2 domain. Sci. Signal. 2, ra8 (2009).

    Article  Google Scholar 

  56. Shi, P. et al. Persistent stimulation with interleukin-17 desensitizes cells through SCFβ-TrCP–mediated degradation of Act1. Sci. Signal. 4, ra73 (2011).

    Article  Google Scholar 

  57. Austin, H.A. III., Muenz, L.R., Joyce, K.M., Antonovych, T.T. & Balow, J.E. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int. 25, 689–695 (1984).

    Article  Google Scholar 

  58. Moreth, K. et al. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J. Clin. Invest. 120, 4251–4272 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Flavell (Yale University) for providing Il17a-deficient mice. This work is supported by grants from National Natural Science Foundation of China and 973 program (30930084, 2010CB529705, 91029708 and 30871298), Chinese Academy of Sciences (KSCX2-YW-R-146) and the Science and Technology Commission of Shanghai Municipality (10JC1416600) to Y.Q.; as well as National Natural Science Foundation of China (30971632 and 81025016), Chinese Ministry of Health (201202008) and the Program of the Shanghai Commission of Science and Technology (10JC1409300) to N.S.

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  1. Shu Zhu and Wen Pan: These authors contributed equally to this work.

Authors and Affiliations

  1. The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Shu Zhu, Wen Pan, Xinyang Song, Yan Liu, Xinrui Shao, Yufang Shi, Nan Shen & Youcun Qian

  2. Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yuanjia Tang & Nan Shen

  3. Division of Rheumatology and the Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Dong Liang, John B Harley & Nan Shen

  4. Guanghua Rheumatology Hospital, Shanghai, China

    Dongyi He

  5. Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Honglin Wang

  6. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada

    Wenjun Liu

  7. US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA

    John B Harley

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Contributions

S.Z. and Y.Q. designed the experiments and wrote the manuscript. S.Z. and W.P. conducted most of the experiments and analyzed the data. W.P., N.S. and J.B.H. edited the manuscript. X. Song and Y.L. helped with mouse experiments. X. Shao helped with molecular cloning. Y.S., Y.T. and D.L. provided technical support. H.W. provided Il17a−/− mice. W.L. performed Ingenuity Pathway Analyses. N.S. and D.H. provided clinical samples. Y.Q. and N.S. supervised the study.

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Correspondence to Nan Shen or Youcun Qian.

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Zhu, S., Pan, W., Song, X. et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nat Med 18, 1077–1086 (2012). https://doi.org/10.1038/nm.2815

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