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

Objective 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). Methods 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. Results 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. Conclusion 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.