HMGB1-mediated endoplasmic reticulum stress in monocyte-derived dendritic cells regulates CD4+ T cell immune...

Myasthenia gravis (MG) is an autoimmune disorder characterized by immune dysregulation at the neuromuscular junction. Monocyte-derived dendritic cells (moDCs) are increasingly recognized as key drivers of MG pathogenesis; however, the mechanisms that govern their dysfunction remain incompletely understood.

This study integrated human genetics, patient immunophenotyping, and therapeutic evaluation in the experimental autoimmune myasthenia gravis (EAMG) model. Monocytes were isolated and differentiated into moDCs to assess the effects of HMGB1 and its inhibitor, 18α-glycyrrhetinic acid (18α-GA), on the expression profiles, phenotypes, and functions of moDCs. Therapeutic efficacy was further assessed in EAMG using 18α-GA, HMGB1 neutralizing antibody, and adoptive transfer of 18α-GA-induced tolerogenic moDCs.

Mendelian randomization (MR) analyses revealed bidirectional causality between MG and moDCs. MG patients exhibited elevated plasma HMGB1 levels and mature phenotypes of moDCs. Mechanistically, HMGB1 activated the IRE1α/XBP1 and NF-κB pathways in moDCs through the engagement of TLR4, thereby inducing endoplasmic reticulum (ER) stress, promoting the activation of moDCs, and driving an imbalance in CD4+ T cell immune responses. Through a multitargeted mechanism of action, 18α-GA effectively inhibited both the IRE1α/XBP1 and NF-κB pathways in moDCs, thereby blunting ER stress and driving the differentiation of moDCs toward tolerogenic phenotypes. The minimal effective dose of 18α-GA alleviated EAMG by counteracting HMGB1-driven, moDC-mediated CD4+ T cell dysfunction, and showed better therapeutic performance compared with HMGB1 neutralizing antibody. Moreover, the adoptive transfer of 18α-GA-induced tolerogenic moDCs was effective in treating EAMG.

HMGB1-mediated ER stress reprogrammed moDCs via the IRE1α/XBP1 and NF-κB pathways to promote pathogenic CD4+ T cell responses in MG. Targeting the HMGB1-ER stress axis in moDCs could restore immune balance and represent a promising therapeutic strategy for MG.