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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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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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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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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DOI: https://doi.org/10.1038/nm.2815
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