Abstract
OBJECTIVE-The implication of innate immunity in type 1 diabetes development has long been proposed. High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was recently recognized to be a potent innate inflammatory mediator when released extracellularly. We sought to test the hypothesis that HMGB1 acts as an innate immune mediator implicated in type 1 diabetes pathogenesis. RESEARCH DESIGN AND METHODS-Eight- and 12-week- old NOD mice were treated with an HMGB1 neutralizing antibody once a week until 25 weeks of age 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 dendritic cell maturation and stimulating mac- rophage activation. Blockade of HMGB1 significantly inhibited insulitis progression and diabetes development in both 8- and 12-week-old NOD mice. HMGB1 antibody treatment decreased the number and maturation of pancreatic lymph node (PLN) CD11c ++CD11b + dendritic cells, a subset of dendritic cells probably associated with autoantigen presentation to naive T- cells, but increased the number for PLN CD4 +Foxp3 + regulatory T-cells. Blockade of HMGB1 also decreased splenic dendritic cell allo-stimulatory capability associated with increased tolergenic CD11c +CD8a + dendritic cells. Interestingly, the number of CD8 +interferon-γ + (Tc1) T-cells was increased in the PLNs and spleen after blockade of HMGB1, which could be associated with retarded migration of activated autoreactive T-cells into the pancreatic islets. CONCLUSIONS-Extracellular HMGB1 functions as a potent innate immune mediator contributing to insulitis progression and diabetes onset.
Original language | English (US) |
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Pages (from-to) | 2118-2127 |
Number of pages | 10 |
Journal | Diabetes |
Volume | 57 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2008 |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism