title: Type I IFN inhibits innate IL-10 production in macrophages through histone deacetylase 11 by downregulating microRNA-145.
abstract: Innate immune responses must be tightly regulated to avoid overactivation and subsequent inflammatory damage to host tissue while eliminating invading pathogens. IL-10 is a crucial suppressor of inflammatory responses and its expression is under precise regulation involving complex regulatory networks and multiple feedback loops. MicroRNAs are now emerging as critical regulators in immune response. Our previous work showed that miR-143/145 cluster was markedly downregulated in macrophages upon vesicular stomatitis virus infection. However, the particular role of miR-143/145 cluster in the regulation of innate immune response remains unknown. In this study, we found that miR-143/145 cluster expression was also downregulated dramatically by TLR signals in macrophages, which was dependent on the subsequent type I IFN (IFN-I) production and downstream IFN-I receptor-JAK1-STAT1 signal cascade. Further studies demonstrated that miR-145, but not miR-143, promoted IL-10 expression in TLR4-triggered macrophages through directly targeting the epigenetic Il10 gene silencer histone deacetylase 11. Therefore, we demonstrate that miR-145, downregulated by IFN-I, targets histone deacetylase 11 to promote innate IL-10 expression in macrophages. Our findings suggest a new IFN-I-mediated negative feedback loop in the fine-tuning of innate IL-10 production that creates precise coordination of innate immune responses.
authors: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors: Li
authors: L
authors: Lin
authors: Jin
authors: J
authors: Hou
authors: Feng
authors: F
authors: Ma
authors: Pin
authors: P
authors: Wang
authors: Xingguang
authors: X
authors: Liu
authors: Nan
authors: N
authors: Li
authors: Jianli
authors: J
authors: Wang
authors: Qingqing
authors: Q
authors: Wang
authors: Xuetao
authors: X
authors: Cao
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D053613:Janus Kinase 1 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic; D000097905:Roundabout Proteins
chemical_list: D006655:Histone Deacetylases; D007370:Interferon Type I; D016753:Interleukin-10; D018664:Interleukin-12; D053613:Janus Kinase 1; D008565:Membrane Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; D051193:Toll-Like Receptors; C543499:MIRN145a microRNA, mouse; C532884:MIRN143 microRNA, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C528111:Hdac11 protein, mouse