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

• Published in: Frontiers in immunology Vol. 11; p. 616141
• Main Authors: Hiramatsu-Asano, Sumie, Sunahori-Watanabe, Katsue, Zeggar, Sonia, Katsuyama, Eri, Mukai, Tomoyuki, Morita, Yoshitaka, Wada, Jun
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 26.01.2021
• Subjects: Immunology; lupus nephritis; miR-223-3p; MRL/MpJ-Faslpr/J mice; S1pr1; S1PR1+CD4+ T cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.616141

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.