Extracellular HMGB1 acts as an innate immune-mediator to enhance autoimmune progression and diabetes onset in NOD mice
- Junyan Han1,
- Jinxin Zhong1,
- Wenzhong Wei1,
- Ying Wang1,
- Yafei Huang1,
- Ping Yang1,
- Sharad Purohit1,
- Zheng Dong2,
- Mong-Heng Wang3,
- Jin-Xiong She1,
- Feili Gong4,
- David M Stern5 and
- Cong-Yi Wang (cwang{at}mcg.edu)1
- 1Center for Biotechnology and Genomic Medicine, Department of Pathology, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, GA 30912, USA
- 2Depatment of Cell Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA
- 3Department of Physiology, Medical College of Georgia, Augusta, GA 30912, USA
- 4Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
- 5University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
Abstract
Objective: The implication of innate immunity in T1D development has long been proposed. HMGB1, an evolutionarily conserved chromosomal protein, was recently recognized to be a potent innate inflammatory mediator when released extracellularly. We sought to test the hypothessis that HMGB1 acts as an innate immune-mediator implicated in T1D pathogenesis.
Research Design and Methods: 8wk- and 12wk-old NOD mice were treated with an HMGB1 neutralizing antibody once a week till 25wk-old and monitored for insulitis progression and diabetes onset. The underlying mechanisms of HMGB1 regulation of autoimmune response were further explored.
Results: During autoimmunity, HMGB1 can be passively released from damaged pancreatic β cells and actively secreted by islet infiltrated immune cells. Extracellular HMGB1 is potent in inducing NOD DC maturation and stimulating macrophage activation. Blockade of HMGB1 significantly inhibited insulitis progression and diabetes development both in 8wk- and 12wk-old NOD mice. HMGB1 antibody treatment decreased the number and maturation of pancreatic lymph node (PLN) CD11c++CD11b+ DCs, a subset of DCs probably associated with auto-antigen presentation to naïve T cells, but increased the number for PLN CD4+Foxp3+ regulatory T cells. Blockade of HMGB1 also decreased splenic DC allo-stimulatory capability associated with increased tolergenic CD11c+CD8a+ DCs. Interestingly, the number of CD8+IFNγ+ (Tc1) T cells was increased in the PLN and spleen after blockade of HMGB1, which could be associated with retarded migration of activated autoreactive T cells into the pancreatic islets.
Conclusion: Extracellular HMGB1 functions as a potent innate immune-mediator contributing to insulitis progression and diabetes onset.
Footnotes
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- Received November 7, 2007.
- Accepted May 7, 2008.
- Copyright © American Diabetes Association
