miR-23b-3p deficiency exacerbates immune dysregulation in immunoglobulin A vasculitis by enhancing TLR4-mediated dendritic cell activation.

Abstract

MicroRNAs (miRNAs) play critical roles in regulating immune cell differentiation and maintaining innate and adaptive immune homeostasis. The aim of this study was to determine the mechanisms by which miR-23b-3p modulates crosstalk between innate and adaptive immunity in immunoglobulin A (IgA) vasculitis (IgAV) and to evaluate its therapeutic potential. An IgAV rat model and in vitro cell culture systems were established to assess the effects of miR-23b-3p on dendritic cell (DC) maturation and function via Toll-like receptor 4 (TLR4) signalling and to determine the subsequent impact on T follicular helper (Tfh) cell differentiation mediated by cytokine secretion. IgAV rats exhibited significantly increased TLR4 expression in peripheral blood mononuclear cells and spleen tissue, accompanied by reduced miR-23b-3p expression. Mechanistic analyses demonstrated that miR-23b-3p directly targeted TLR4 to suppress its expression. In vivo overexpression of miR-23b-3p ameliorated IgAV manifestations, as evidenced by reduced TLR4 expression on DCs, diminished Tfh cell differentiation, and decreased serum levels of IgA, interleukin (IL)-6, and IL-12. Notably, TLR4 silencing reversed miR-23b-3p inhibitor-induced DC hyperactivation and aberrant Tfh cell differentiation. miR-23b-3p regulates DC maturation and function and subsequent Tfh differentiation in a TLR4-dependent manner. miR-23b-3p deficiency aggravates IgAV by promoting pathogenic DC-Tfh axis activation, whereas restoration of miR-23b-3p expression attenuates immune dysregulation, suggesting a potential therapeutic strategy for IgAV.