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

Front Immunol. 2021 Jan 26:11:616141. doi: 10.3389/fimmu.2020.616141. eCollection 2020.

Abstract

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-Faslpr /J mice. We performed 3' untranslated region (UTR) luciferase reporter gene assay using human umbilical vein endothelial cells (HUVECs). We generated the B6-Mir223-/-Faslpr/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-Faslpr /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-/-Faslpr/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+/+Faslpr/lpr mice by flow cytometry. B6-Mir223-/-Faslpr/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.

Keywords: MRL/MpJ-Faslpr/J mice; S1PR1+CD4+ T cells; S1pr1; lupus nephritis; miR-223-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Gene Expression Regulation / immunology
  • Human Umbilical Vein Endothelial Cells / immunology
  • Humans
  • Lupus Nephritis / immunology*
  • Mice
  • Mice, Inbred MRL lpr
  • MicroRNAs / immunology
  • MicroRNAs / metabolism*
  • Sphingosine-1-Phosphate Receptors / immunology
  • Sphingosine-1-Phosphate Receptors / metabolism*

Substances

  • MIRN223 microRNA, human
  • MIRN223 microRNA, mouse
  • MicroRNAs
  • Sphingosine-1-Phosphate Receptors