Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability.
Animals
Antibodies, Neutralizing
/ pharmacology
Blotting, Western
Cells, Cultured
Colitis
/ immunology
Diabetes Mellitus, Type 1
/ immunology
Female
HMGB1 Protein
/ antagonists & inhibitors
Humans
Islets of Langerhans Transplantation
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Phosphatidylinositol 3-Kinases
/ metabolism
T-Lymphocytes, Regulatory
/ metabolism
Beta cell mass turnover
Diabetes reversal
HMGB1
High-mobility group box 1
Islet transplantation
Regulatory T cells
Type 1 diabetes
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
08
11
2019
accepted:
15
01
2020
pubmed:
20
2
2020
medline:
1
6
2021
entrez:
20
2
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 32072192
doi: 10.1007/s00125-020-05105-8
pii: 10.1007/s00125-020-05105-8
pmc: PMC7145789
doi:
Substances chimiques
Antibodies, Neutralizing
0
HMGB1 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
987-1001Subventions
Organisme : National Natural Science Foundation of China
ID : 91749207
Pays : International
Organisme : Ministry of Science and Technology of the People's Republic of China
ID : 2017YFC1309603
Pays : International
Organisme : NHC Drug Discovery Program
ID : 2017ZX09304022-07
Pays : International
Organisme : Department of Science and Technology of Hubei porvince
ID : 2017ACA096
Pays : International
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