Decreased microRNA‐142‐3p/5p expression causes CD4+ T cell activation and B cell hyperstimulation in systemic lupus erythematosus

Abstract

To examine the role of microRNA-142-3p/5p (miR-142-3p/5p) in the development of autoimmunity in patients with systemic lupus erythematosus (SLE). MicroRNA-142-3p/5p expression levels were determined by real-time quantitative polymerase chain reaction, and potential target genes were verified using luciferase reporter gene assays. The effects of miR-142-3p/5p on T cell function were assessed by transfection with miR-142-3p/5p inhibitors or mimics. Histone modifications and methylation levels within a putative regulatory region of the miR-142 locus were detected by chromatin immunoprecipitation assay and bisulfite sequencing, respectively. We confirmed that miR-142-3p and miR-142-5p were significantly down-regulated in SLE CD4+ T cells compared with healthy controls and observed that miR-142-3p/5p levels were inversely correlated with the putative SLE-related targets signaling lymphocytic activation molecule-associated protein (SAP), CD84, and interleukin-10 (IL-10). We demonstrated that miR-142-3p and miR-142-5p directly inhibit SAP, CD84, and IL-10 translation, and that reduced miR-142-3p/5p expression in CD4+ T cells can significantly increase protein levels of these target genes. Furthermore, inhibiting miR-142-3p/5p in healthy donor CD4+ T cells caused T cell overactivation and B cell hyperstimulation, whereas overexpression of miR-142-3p/5p in SLE CD4+ T cells had the opposite effect. We also observed that the decrease in miR-142 expression in SLE CD4+ T cells correlated with changes to histone modifications and DNA methylation levels upstream of the miR-142 precursor sequence. The results of this study indicate that reduced expression of miR-142-3p/5p in the CD4+ T cells of patients with SLE causes T cell activity and B cell hyperstimulation.