Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus

Abstract

Objective: microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE.

Methods: We determined the miR-152-3p expression profiles in CD4⁺ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4⁺ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88).

Results: The obtained findings revealed that miR-152-3p was highly-expressed in CD4⁺ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4⁺ T cells and but also to restrain their cellular inflammation, which were also validated in vivo.

Conclusion: Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4⁺ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.

Keywords: CD4+ T cells; DNA methyltransferase 1; Inflammatory response; Myeloid differentiation primary response gene 88; Systemic lupus erythematosus; Toll-like receptor; microRNA-152-3p.