title: Interleukin-17 (IL-17)-induced microRNA 873 (miR-873) contributes to the pathogenesis of experimental autoimmune encephalomyelitis by targeting A20 ubiquitin-editing enzyme.
abstract: Interleukin 17 (IL-17), produced mainly by T helper 17 (Th17) cells, is increasingly recognized as a key regulator in various autoimmune diseases, including human multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although several microRNAs (miRNAs) with aberrant expression have been shown to contribute to the pathogenesis of MS and EAE, the mechanisms underlying the regulation of abnormal miRNA expression in astrocytes upon IL-17 stimulation remain unclear. In the present study, we detected the changes of miRNA expression profiles both in the brain tissue of EAE mice and in cultured mouse primary astrocytes stimulated with IL-17 and identified miR-873 as one of the co-up-regulated miRNAs in vivo and in vitro. The overexpression of miR-873, demonstrated by targeting A20 (TNFα-induced protein 3, TNFAIP3), remarkably reduced the A20 level and promoted NF-κB activation in vivo and in vitro as well as increasing the production of inflammatory cytokines and chemokines (i.e. IL-6, TNF-α, MIP-2, and MCP-1/5). More importantly, silencing the endogenous miR-873 or A20 gene with lentiviral vector of miR-873 sponge (LV-miR-873 sponge) or short hairpin RNA (shRNA) of A20 (LV-A20 shRNA) in vivo significantly lessened or aggravated inflammation and demyelination in the central nervous system (CNS) of EAE mice, respectively. Taken together, these findings indicate that miR-873 induced by IL-17 stimulation promotes the production of inflammatory cytokines and aggravates the pathological process of EAE mice through the A20/NF-κB pathway, which provides a new insight into the mechanism of inflammatory damage in MS.
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Fengxia
authors.initials: F
authors.lastname: He
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Pang
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Qiu
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Shan
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Yanlai
authors.initials: Y
authors.lastname: Lu
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Department of Microbiology and Immunology, Nanjing Medical University, Hanzhong Road 140, Nanjing, Jiangsu 210029, China wangyw1508@njmu.edu.cn.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003711:Demyelinating Diseases; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D020413:3' Untranslated Regions; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; C000593791:MIRN873 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
keywords: A20; Astrocyte; Cytokine; Experimental Autoimmune Encephalomyelitis; Interleukin 17A (IL-17 or IL-17A); MicroRNA-873; Multiple Sclerosis; NF-kappaB