Deletion Of Mir223 Exacerbates Lupus Nephritis By Targeting S1pr1 In Fas(Lpr/Lpr) Mice

ObjectiveThe 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.MethodsWe 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.ResultsIn 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.ConclusionUnexpectedly, 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.