Toll-like receptor 4 on islet beta cells senses expression changes in high-mobility group box 1 and contributes to the initiation of type 1 diabetes.
10.3858/emm.2012.44.4.021
- Author:
Min LI
1
;
Lujun SONG
;
Xiaodong GAO
;
Wenju CHANG
;
Xinyu QIN
Author Information
1. Department of General Surgery, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200032, China. qin.xinyu@zs-hospital.sh.cn
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
diabetes mellitus, type 1;
HMGB1 protein;
islets of Langerhans;
mice, inbred NOD;
toll-like receptor 4
- MeSH:
Animals;
Diabetes Mellitus, Type 1/immunology/*metabolism/pathology;
Female;
Gene Expression Regulation;
Glucagon-Secreting Cells/immunology/metabolism/pathology;
HMGB1 Protein/*genetics/metabolism;
Humans;
Immunity, Innate;
Insulin-Secreting Cells/immunology/metabolism/*pathology;
Macrophages/immunology/pathology;
Mice;
Mice, Inbred C57BL;
Mice, Inbred NOD;
Necrosis;
Protein Binding;
Signal Transduction;
Toll-Like Receptor 4/*antagonists & inhibitors/genetics/immunology
- From:Experimental & Molecular Medicine
2012;44(4):260-267
- CountryRepublic of Korea
- Language:English
-
Abstract:
Type 1 diabetes mellitus is caused by the autoimmune destruction of beta cells within the islets. In recent years, innate immunity has been proposed to play a key role in this process. High-mobility group box 1 (HMGB1), an inflammatory trigger in a number of autoimmune diseases, activates proinflammatory responses following its release from necrotic cells. Our aim was to determine the significance of HMGB1 in the natural history of diabetes in non-obese diabetic (NOD) mice. We observed that the rate of HMGB1 expression in the cytoplasm of islets was much greater in diabetic mice compared with non-diabetic mice. The majority of cells positively stained for toll-like receptor 4 (TLR4) were beta cells; few alpha cells were stained for TLR4. Thus, we examined the effects of anti-TLR4 antibodies on HMGB1 cell surface binding, which confirmed that HMGB1 interacts with TLR4 in isolated islets. Expression changes in HMGB1 and TLR4 were detected throughout the course of diabetes. Our findings indicate that TLR4 is the main receptor on beta cells and that HMGB1 may signal via TLR4 to selectively damage beta cells rather than alpha cells during the development of type 1 diabetes mellitus.
