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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.

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