Deletion of Mir223 Exacerbates Lupus Nephritis by Targeting S1pr1 in Fas lpr/lpr Mice.

Autor:	Hiramatsu-Asano S; Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.; Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan., Sunahori-Watanabe K; Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan., Zeggar S; Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan., Katsuyama E; Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan., Mukai T; Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan., Morita Y; Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan., Wada J; Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Jan 26; Vol. 11, pp. 616141. Date of Electronic Publication: 2021 Jan 26 (Print Publication: 2020).
DOI:	10.3389/fimmu.2020.616141
Abstrakt:	Objective: The micro RNAs (miRNAs) and their target mRNAs are differentially expressed in various immune-mediated cells. Here, we investigated the role of Mir223 and sphingosine-1-phosphate receptor 1 ( S1pr1 ) in the pathogenesis of systemic lupus erythematosus. Methods: We analyzed miRNA and mRNA profiling data of CD4 + splenic T cells derived from MRL/MpJ- Fas lpr /J mice. We performed 3' untranslated region (UTR) luciferase reporter gene assay using human umbilical vein endothelial cells (HUVECs). We generated the B6- Mir223 -/- Fas lpr/lpr mice and the lupus phenotypes were analyzed. Results: In CD4 + splenic T cells, we identified upregulation of miR-223-3p and downregulation of the possible target, S1pr1 by RNA sequencing of MRL/MpJ- Fas lpr /J mice. The transfection with miR-223-3p mimic significantly suppressed a luciferase activity in HUVEC treated with a Lentivirus vector containing 3' UTR of S1pr1 . The mRNA levels of S1pr1 were significantly decreased after miR-223-3p overexpression. In B6- Mir223 -/- Fas lpr/lpr mice, the proportion of CD3 + T cells, CD3 + CD4 - CD8 - cells, B cells, plasma cells, and S1PR1 + CD4 + T cells in the spleen was significantly increased compared with that in B6- Mir223 +/+ Fas lpr/lpr mice by flow cytometry. B6- Mir223 -/- Fas lpr/lpr mice demonstrated the elevation of glomerular and renal vascular scores associated with enhanced intraglomerular infiltration of S1PR1 + CD4 + T cells. Conclusion: Unexpectedly, the deletion of Mir223 exacerbated the lupus phenotypes associated with increased population of S1PR1 + CD4 + T in spleen and the enhanced infiltration of S1PR1 + CD4 + T cells in inflamed kidney tissues, suggesting compensatory role of Mir223 in the pathogenesis of lupus nephritis. Competing Interests: SH-A and TM receive scholarship donations from Chugai and Ayumi. KS-W receives speaker honoraria from Chugai. YM receives scholarship donations from Chugai and Ayumi and speaker honoraria from Eli Lilly. JW receives speaker honoraria from Astra Zeneca, Daiichi Sankyo, MSD, Novartis, Tanabe Mitsubishi, Taisho Toyama and receives grant support from Baxter, Chugai, Dainippon Sumitomo, Ono, and Teijin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Hiramatsu-Asano, Sunahori-Watanabe, Zeggar, Katsuyama, Mukai, Morita and Wada.)
Databáze:	MEDLINE
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