Mettl3 induced miR‐338‐3p expression in dendritic cells promotes antigen‐specific Th17 cell response via regulation of Dusp16

Abstract

Pathogenic Th17 cells are critical drivers of multiple autoimmune diseases, including uveitis and its animal model, experimental autoimmune uveitis (EAU). However, how innate immune signals modulate pathogenic Th17 responses remains largely unknown. Here, we showed that miR‐338‐3p endowed dendritic cells (DCs) with an increased ability to activate interphotoreceptor retinoid‐binding protein (IRBP)1–20‐specific Th17 cells by promoting the production of IL‐6, IL‐1β, and IL‐23. In vivo administration of LV‐miR‐338‐infected DCs promoted pathogenic Th17 responses and exacerbated EAU development. Mechanistically, dual‐specificity phosphatase 16 (Dusp16) was a molecular target of miR‐338‐3p. miR‐338‐3p repressed Dusp16 and therefore strengthened the mitogen‐activated protein kinase (MAPK) p38 signaling, resulting in increased production of Th17‐polarizing cytokines and subsequent pathogenic Th17 responses. In addition, methyltransferase like 3 (Mettl3), a key m6A methyltransferase, mediated the upregulation of miR‐338‐3p in activated DCs. Together, our findings identify a vital role for Mettl3/miR‐338‐3p/Dusp16/p38 signaling in DCs‐driven pathogenic Th17 responses and suggest a potential therapeutic avenue for uveitis and other Th17 cell‐related autoimmune disorders.

Role of microRNAs in Immune Regulation with Translational and Clinical Applications

“…miR-150 and miR-223 are involved in the regulation of antigen presentation ability, while miR-29c, miR-146 and miR-155 affect the survival of DCs [42]. Up-regulation of miR-338 in DCs led to pathogenic Th17 responses and exacerbated the development of EAU in an animal model [43]. Overexpression of miR-200b in human peripheral blood mononuclear cells (PBMCs) resulted in significantly reduced numbers of protruding veils in mature DCs that are critical for antigen-specific T-cell activation [44].…”

M6A modification and T cells in adipose tissue inflammation

“…It has been demonstrated that Mettl3 upregulates miR-338-3p in activated DCs, which inhibits Dusp16 and enhances mitogenactivated protein kinase (MAPK) p38 signaling, increasing the production of Th17-polarizing cytokines and ultimately leading to a pathogenic Th17 response (Figure 2). 108 In addition, based on the in-depth understanding of the mechanism of m6A modification in obesity-related inflammation, attempts can be made to develop therapeutic strategies targeting m6A modification, such as drugs targeting m6A methylase or demethylase, small molecule compounds regulating the level of m6A modification, etc., to achieve the precise modulation of inflammatory responses and the treatment of obesity and its related metabolic diseases. Through these modulations targeting m6A modifications, it may be possible to effectively regulate the development of obesity-related inflammation.…”

“…It has been demonstrated that Mettl3 upregulates miR‐338‐3p in activated DCs, which inhibits Dusp16 and enhances mitogen‐activated protein kinase (MAPK) p38 signaling, increasing the production of Th17‐polarizing cytokines and ultimately leading to a pathogenic Th17 response (Figure 2). 108 Overall, the interactions between DCs and T cells regulated by m6A have lacked direct studies on adipose tissue inflammation, but the same elements of studies on inflammation in other tissues also play an important role in the development of obesity‐associated inflammation and m6A modification may be one of the primary mechanisms regulating these interactions. A deeper understanding of these mechanisms will help to unravel the pathogenesis of obesity and provide a theoretical basis for the development of new therapeutic strategies.…”