PMID- 29544526 OWN - NLM STAT- MEDLINE DCOM- 20190415 LR - 20190415 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 20 IP - 1 DP - 2018 Mar 15 TI - Mice with miR-146a deficiency develop severe gouty arthritis via dysregulation of TRAF 6, IRAK 1 and NALP3 inflammasome. PG - 45 LID - 10.1186/s13075-018-1546-7 [doi] LID - 45 AB - BACKGROUND: MicroRNAs (miRNAs) serve as important regulators of inflammatory and immune responses and are implicated in several immune disorders including gouty arthritis. The expression of miR-146a is upregulated in the peripheral blood mononuclear cells of patients with inter-critical gout when compared to normouricemic and hyperuricemic controls and those patients with acute gout flares. However, the role of miR-146a in the development of gout remains unknown. Here, we used miR-146a knockout (KO) mice to test miR-146a function in a monosodium urate (MSU)-induced gouty arthritis model. METHODS: The footpad or ankle joint of miR-146a KO and wild-type (WT) mice were injected with an MSU suspension to induce acute gouty arthritis. Bone marrow-derived macrophages (BMDMs) were stimulated with MSU and the gene expression of miR-146a; interleukin 1 beta (IL-1beta); tumor necrosis factor-alpha (TNF-alpha); and the NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome was evaluated. TNF-alpha and IL-1beta protein levels in BMDMs were assessed by fluorescence-activated cell sorting and western blot analyses. Gene and protein levels of TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase (IRAK1), the targets of miR-146a, were also measured. RESULTS: Significantly increased paw swelling and index and ankle joint swelling were observed in miR-146a KO mice compared to WT controls after MSU treatment. MiR-146a expression in BMDMs from WT mice was dramatically upregulated at 4 h following MSU stimulation. Additionally, the expression of IL-1beta, TNF-alpha, and NALP3 was higher in BMDMs from miR-146a KO mice after exposure to MSU crystals compared to those from WT mice. Consistent with the observed gene expression, the IL-1beta and TNF-alpha proteins were upregulated in miR-146a KO mice. Additionally quantitative RT-PCR and western blot demonstrated that TRAF6 and IRAK1 were dramatically upregulated in BMDMs from miR-146 KO mice compared to those from WT mice. CONCLUSIONS: Collectively, these observations suggest that miR-146a provides negative feedback regulation of gouty arthritis development and lack of miR-146a enhances gouty arthritis via upregulation of TRAK6, IRAK-1, and the NALP3 inflammasome function. FAU - Zhang, Quan-Bo AU - Zhang QB AUID- ORCID: 0000-0001-8559-1927 AD - Department of Geriatrics, Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan, 637000, People's Republic of China. quanbozhang@126.com. AD - Henry Ford Immunology Program, Department of Dermatology and Internal Medicine, Henry Ford Health System, One Ford Place, 1D-Rm. 31, Detroit, MI, 48202-2689, USA. quanbozhang@126.com. FAU - Qing, Yu-Feng AU - Qing YF AD - Department of Rheumatology and Immunology, Affiliated Hospital, North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan, 637000, People's Republic of China. FAU - Yin, Cong-Cong AU - Yin CC AD - Henry Ford Immunology Program, Department of Dermatology and Internal Medicine, Henry Ford Health System, One Ford Place, 1D-Rm. 31, Detroit, MI, 48202-2689, USA. AD - Department of Internal Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China. FAU - Zhou, Li AU - Zhou L AD - Henry Ford Immunology Program, Department of Dermatology and Internal Medicine, Henry Ford Health System, One Ford Place, 1D-Rm. 31, Detroit, MI, 48202-2689, USA. FAU - Liu, Xian-Shuang AU - Liu XS AD - Department of Neurology, Henry Ford Health System, Detroit, MI, USA. FAU - Mi, Qing-Sheng AU - Mi QS AD - Henry Ford Immunology Program, Department of Dermatology and Internal Medicine, Henry Ford Health System, One Ford Place, 1D-Rm. 31, Detroit, MI, 48202-2689, USA. qmi1@hfhs.org. FAU - Zhou, Jing-Guo AU - Zhou JG AD - Department of Rheumatology and Immunology, Affiliated Hospital, North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan, 637000, People's Republic of China. jgzhou@nsmc.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180315 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (MicroRNAs) RN - 0 (Mirn146 microRNA, mouse) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (TNF Receptor-Associated Factor 6) RN - EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases) RN - EC 2.7.11.1 (Irak1 protein, mouse) SB - IM MH - Animals MH - Arthritis, Gouty/*metabolism/pathology MH - Cells, Cultured MH - Interleukin-1 Receptor-Associated Kinases/*biosynthesis MH - Macrophages/metabolism/pathology MH - Mice MH - Mice, Knockout MH - MicroRNAs/*metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/*biosynthesis MH - *Severity of Illness Index MH - TNF Receptor-Associated Factor 6/*biosynthesis PMC - PMC5855987 OTO - NOTNLM OT - Gout OT - IRAK1 OT - NALP3 inflammasome OT - TRAF6 OT - miR-146a COIS- ETHICS APPROVAL: Handing of mice and experimental procedures were in accordance with requirements of the Institutional Animal Care and Use Committee and this study was granted permission by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/03/17 06:00 MHDA- 2019/04/16 06:00 PMCR- 2018/03/15 CRDT- 2018/03/17 06:00 PHST- 2017/09/28 00:00 [received] PHST- 2018/02/18 00:00 [accepted] PHST- 2018/03/17 06:00 [entrez] PHST- 2018/03/17 06:00 [pubmed] PHST- 2019/04/16 06:00 [medline] PHST- 2018/03/15 00:00 [pmc-release] AID - 10.1186/s13075-018-1546-7 [pii] AID - 1546 [pii] AID - 10.1186/s13075-018-1546-7 [doi] PST - epublish SO - Arthritis Res Ther. 2018 Mar 15;20(1):45. doi: 10.1186/s13075-018-1546-7.