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

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 pr...

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Published inFrontiers 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
LanguageEnglish
Published Frontiers Media S.A 26.01.2021
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Summary: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.
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Reviewed by: Yasunori Iwata, Kanazawa University, Japan; S. Ansar Ahmed, Virginia Tech, United States
Edited by: Kunihiro Ichinose, Nagasaki University, Japan
This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2020.616141