Hmgb1 acts as an innate alarmin implicated in the pathogenesis of type 1 diabetes

Hmgb1 is an evolutionarily conserved chromosomal protein. It was recently re-discovered to be a potent innate alarmin implicated in both innate and adaptive immune response when it is present extracellularly. Hmgb1 can be either passively released by damaged cells or actively secreted by activated immune cells such as dendritic cells (DCs) and macrophages. Previous studies including ours provided strong evidence indicating a role for Hmgb1 in autoimmune diabetes by regulation of DCs, T effector cells, and regulatory T-cells (Tregs), while the related underlying mechanisms have not been fully addressed. Here we employed NOD mice as a model to dissect the impact of blocking HMGB1 on prevention and treatment of type 1 diabetes. It was interestingly noted that blockade of Hmgb1 passively released during β-mass turnover not only prevents autoimmune progression but also delays diabetes onset. HMGB1 can be served as a therapeutic target to prevent β cell destruction by recurrent autoimmunity after islet transplantation, and to reverse type 1 diabetes in newly diagnosed subjects. Mechanistic studies revealed that extracellular Hmgb1 impairs the stability of Tregs through regulation of PI3K-Akt- mTOR signaling, thereby promoting STAT1 activation. As a result, the activated STAT1 then enhances the transcription of T-bet, a critical transcription factor for T-helper type 1 (Th1) cells, which skews functional Tregs into a Th1-like type of Tregs and eventually loss of Foxp3 expression. Collectively, our data provide pivotal information for understanding of the role of Hmgb1 in type 1 diabetes pathogenesis.