TY - JOUR
T1 - Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability
AU - Zhang, Jing
AU - Chen, Longmin
AU - Wang, Faxi
AU - Zou, Yuan
AU - Li, Jingyi
AU - Luo, Jiahui
AU - Khan, Faheem
AU - Sun, Fei
AU - Li, Yang
AU - Liu, Jing
AU - Chen, Zhishui
AU - Zhang, Shu
AU - Xiong, Fei
AU - Yu, Qilin
AU - Li, Jinxiu
AU - Huang, Kun
AU - Adam, Bao Ling
AU - Zhou, Zhiguang
AU - Eizirik, Decio L.
AU - Yang, Ping
AU - Wang, Cong Yi
N1 - Funding Information:
This study was supported by the Ministry of Science and Technology (2016YFC1305002 and 2017YFC1309603), the National Natural Science Foundation of China (81471046, 81530024, 91749207, 81920108009, 81770823 and 81670729), NHC Drug Discovery Program (2017ZX09304022-07), the Department of Science and Technology of Hubei State (2017ACA096), the Integrated Innovative Team for Major Human Disease Programs of Tongji Medical College, Huazhong University of Science and Technology, and the Innovative Funding for Translational Research from Tongji Hospital. Acknowledgements
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Aims/hypothesis: High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was rediscovered to be a ‘danger signal’ (alarmin) that alerts the immune system once released extracellularly. Therefore, it has been recognised contributing to the pathogenesis of autoimmune diabetes, but its exact impact on the initiation and progression of type 1 diabetes, as well as the related molecular mechanisms, are yet to be fully characterised. Methods: In the current report, we employed NOD mice as a model to dissect the impact of blocking HMGB1 on the prevention, treatment and reversal of type 1 diabetes. To study the mechanism involved, we extensively examined the characteristics of regulatory T cells (Tregs) and their related signalling pathways upon HMGB1 stimulation. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. Results: Neutralising HMGB1 both delayed diabetes onset and, of particular relevance, reversed diabetes in 13 out of 20 new-onset diabetic NOD mice. Consistently, blockade of HMGB1 prevented islet isografts from autoimmune attack in diabetic NOD mice. Using transgenic reporter mice that carry a Foxp3 lineage reporter construct, we found that administration of HMGB1 impairs Treg stability and function. Mechanistic studies revealed that HMGB1 activates receptor for AGE (RAGE) and toll-like receptor (TLR)4 to enhance phosphatidylinositol 3-kinase (PI3K)–Akt–mechanistic target of rapamycin (mTOR) signalling, thereby impairing Treg stability and functionality. Indeed, high circulating levels of HMGB1 in human participants with type 1 diabetes contribute to Treg instability, suggesting that blockade of HMGB1 could be an effective therapy against type 1 diabetes in clinical settings. Conclusions/interpretation: The present data support the possibility that HMGB1 could be a viable therapeutic target to prevent the initiation, progression and recurrence of autoimmunity in the setting of type 1 diabetes.
AB - Aims/hypothesis: High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was rediscovered to be a ‘danger signal’ (alarmin) that alerts the immune system once released extracellularly. Therefore, it has been recognised contributing to the pathogenesis of autoimmune diabetes, but its exact impact on the initiation and progression of type 1 diabetes, as well as the related molecular mechanisms, are yet to be fully characterised. Methods: In the current report, we employed NOD mice as a model to dissect the impact of blocking HMGB1 on the prevention, treatment and reversal of type 1 diabetes. To study the mechanism involved, we extensively examined the characteristics of regulatory T cells (Tregs) and their related signalling pathways upon HMGB1 stimulation. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. Results: Neutralising HMGB1 both delayed diabetes onset and, of particular relevance, reversed diabetes in 13 out of 20 new-onset diabetic NOD mice. Consistently, blockade of HMGB1 prevented islet isografts from autoimmune attack in diabetic NOD mice. Using transgenic reporter mice that carry a Foxp3 lineage reporter construct, we found that administration of HMGB1 impairs Treg stability and function. Mechanistic studies revealed that HMGB1 activates receptor for AGE (RAGE) and toll-like receptor (TLR)4 to enhance phosphatidylinositol 3-kinase (PI3K)–Akt–mechanistic target of rapamycin (mTOR) signalling, thereby impairing Treg stability and functionality. Indeed, high circulating levels of HMGB1 in human participants with type 1 diabetes contribute to Treg instability, suggesting that blockade of HMGB1 could be an effective therapy against type 1 diabetes in clinical settings. Conclusions/interpretation: The present data support the possibility that HMGB1 could be a viable therapeutic target to prevent the initiation, progression and recurrence of autoimmunity in the setting of type 1 diabetes.
KW - Beta cell mass turnover
KW - Diabetes reversal
KW - HMGB1
KW - High-mobility group box 1
KW - Islet transplantation
KW - Regulatory T cells
KW - Type 1 diabetes
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U2 - 10.1007/s00125-020-05105-8
DO - 10.1007/s00125-020-05105-8
M3 - Article
C2 - 32072192
AN - SCOPUS:85079722953
SN - 0012-186X
VL - 63
SP - 987
EP - 1001
JO - Diabetologia
JF - Diabetologia
IS - 5
ER -
