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Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability (19/02/2020)

Jing Zhang, Longmin Chen, Faxi Wang, Yuan Zou, Jingyi Li, Jiahui Luo, Faheem Khan, Fei Sun, Yang Li, Jing Liu, Zhishui Chen, Shu Zhang, Fei Xiong, Qilin Yu, Jinxiu Li, Kun Huang, Bao-Ling Adam, Zhiguang Zhou, Decio L. Eizirik, Ping Yang, Cong-Yi Wang

Although extracellular high-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, contributes to the pathogenesis of autoimmune diabetes, its impact on the initiation and progression of type 1 diabetes and the underlying mechanisms largely remain to be elucidated. In this issue, Zhang, Chen, et al (https://doi.org/10.1007/s00125-020-05105-8) report that blockade of HMGB1 not only attenuated autoimmune initiation and progression, but also reversed diabetes in a NOD mouse model of new-onset diabetes. Neutralising HMGB1 also prevented islet isografts from recurrent autoimmune attack. Using a Foxp3 lineage tracing model, the authors found that HMGB1 impairs regulatory T cell (Treg) stability and function via altered receptor for AGE (RAGE) and toll-like receptor 4 (TLR4) activation, leading to enhanced phosphatidylinositol 3-kinase (PI3K)–Akt– mechanistic target of rapamycin (mTOR) signalling.  In addition, higher circulating HMGB1 in individuals with type 1 diabetes was noted, which contributed to the impaired Treg stability. According to the authors, their data suggest that HMGB1 could be a viable target for the prevention and treatment of type 1 diabetes in a clinical setting.

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