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

Autor: Bao Ling Adam, Kun Huang, Jiahui Luo, Decio L. Eizirik, Yang Li, Cong-Yi Wang, Fei Xiong, Zhiguang Zhou, Fei Sun, Yuan Zou, Jing Zhang, Zhishui Chen, Qilin Yu, Faheem Ahmed Khan, Faxi Wang, Ping Yang, Longmin Chen, Jingyi Li, Jing Liu, Jinxiu Li, Shu Zhang
Rok vydání: 2020
Předmět:
0301 basic medicine
Endocrinology
Diabetes and Metabolism
Islets of Langerhans Transplantation
medicine.disease_cause
T-Lymphocytes
Regulatory
Autoimmunity
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Mice
Inbred NOD
Islet transplantation
HMGB1 Protein
Cells
Cultured
NOD mice
HMGB1
Mice
Inbred BALB C
FOXP3
Regulatory T cells
Colitis
Endocrinologie
Médecine interne
Type 1 diabetes
medicine.anatomical_structure
030220 oncology & carcinogenesis
Female
Regulatory T cell
Blotting
Western
chemical and pharmacologic phenomena
Article
03 medical and health sciences
High-mobility group box 1
Immune system
Métabolisme
Diabetes mellitus
Internal Medicine
medicine
Animals
Humans
Diabetes reversal
PI3K/AKT/mTOR pathway
Diabétologie
business.industry
Beta cell mass turnover
medicine.disease
Antibodies
Neutralizing
Diabetes Mellitus
Type 1
030104 developmental biology
Immunology
business
Zdroj: Diabetologia
Diabetologia, 63 (5
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-020-05105-8
Popis: 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.
SCOPUS: ar.j
info:eu-repo/semantics/published
Databáze: OpenAIRE
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