2. Academic Validation
  3. Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability

Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability

  • Diabetologia. 2020 May;63(5):987-1001. doi: 10.1007/s00125-020-05105-8.
Jing Zhang 1 2,  Longmin Chen 1 2,  Faxi Wang 1 2,  Yuan Zou 1 2,  Jingyi Li 1,  Jiahui Luo 1 2,  Faheem Khan 1,  Fei Sun 1 2,  Yang Li 1 2,  Jing Liu 1 2,  Zhishui Chen 1 3,  Shu Zhang 1 2,  Fei Xiong 1 2,  Qilin Yu 1,  Jinxiu Li 4,  Kun Huang 5,  Bao-Ling Adam 6,  Zhiguang Zhou 7,  Decio L Eizirik 8,  Ping Yang 9 10,  Cong-Yi Wang 11 12 13
Affiliations

Affiliations

  • 1 The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China.
  • 2 Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Tongji Hospital, Wuhan, China.
  • 4 Shenzhen Third People's Hospital, Shenzhen, Guangdong, China.
  • 5 Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA, USA.
  • 7 Diabetes Center, The Second Xiangya Hospital, Institute of Metabolism and Endocrinology, Central South University, Changsha, China.
  • 8 ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
  • 9 The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China. yangping@tjh.tjmu.edu.cn.
  • 10 Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. yangping@tjh.tjmu.edu.cn.
  • 11 The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Caidian, China. wangcy@tjh.tjmu.edu.cn.
  • 12 Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangcy@tjh.tjmu.edu.cn.
  • 13 Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Tongji Hospital, Wuhan, China. wangcy@tjh.tjmu.edu.cn.
PMID: 32072192 DOI: 10.1007/s00125-020-05105-8
Abstract

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.

Keywords

Beta cell mass turnover; Diabetes reversal; HMGB1; High-mobility group box 1; Islet transplantation; Regulatory T cells; Type 1 diabetes.

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