TREM2 Regulates Microglial Activation via the ERK/p38 Signaling Pathway: Implications for the Pathogenesis of Experimental Autoimmune Uveitis

Purpose: The purpose of this study was to investigate the role of the trigger receptor expressed on myeloid cell 2 (TREM2) in experimental autoimmune uveitis (EAU) and elucidate the mechanisms by which TREM2 modulated inflammation and microglial activation via key signaling pathways. Methods: EAU mouse models and microglial cell BV2 inflammation models were established to explore TREM2 function. TREM2 expression in EAU retinas was detected using public databases and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RT-qPCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), and flow cytometry assessed TREM2 functional phenotypes in autoimmune uveitis. Western blotting and RNA sequencing (RNA-seq) analyzed key signaling pathways' activation to clarify TREM2's molecular mechanisms of inflammatory regulation. Results: TREM2 expression in EAU was elevated at inflammatory peak and reduced during resolution. TREM2 knockdown in inflamed microglia exacerbated inflammation, whereas overexpression alleviated it. TREM2 knockout in EAU mice enhanced retinal vascular leakage, elevated splenic Th1 and Th17 cell proportions, and reduced Treg cell proportions. TREM2 knockdown promoted phosphorylated ERK/p38 activation; overexpression suppressed it. RNA-seq revealed altered retinal mRNA profiles in TREM2 knockout EAU mice, with activation of ERK/p38-associated pathways including the mitogen-activated protein kinase (MAPK) pathway. Conclusions: TREM2 exerted an anti-inflammatory role in EAU pathogenesis, likely by regulating microglial activation and inhibiting the ERK/p38 signaling pathway in these cells.