Extracellular High-Mobility Group Box 1 Acts as an Innate Immune Mediator to Enhance Autoimmune Progression and Diabetes Onset in NOD Mice

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 macrophage 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 naïve 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.

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

“…HMGB1 antibodies (Abs) were produced by immunizing New Zealand white rabbits with rHMGB1 and Abs with neutralizing activities were tested as reported. 23 Affinity-purified antiCD8a (clone 53-6.7) and IL-17A-neutralizing mAb (clone TC11-18H10.1) and control rat IgG were purchased from Biolegend (San Diego, CA, USA). FITC-labeled anti-CD4 (clone GK1.5), FITC-labeled anti-CD8a (53-6.7), PE-labeled anti-IFN-g, PE-labeled anti-IL-17 (clone TC11-18H10), and purified rat anti-mouse CD4 (clone RM4-5) were purchased from BD Pharmingen (San Jose, CA, USA).…”

HMGB1 as an Innate Alarmin Promotes Autoimmune Progress: An Essential Role in the Pathogenesis of Type 1 Diabetes

“…Defects in apoptotic β cell clearance have been considered as an important cause of type 1 diabetes [20][21][22][23][24], although the underlying mechanisms remain elusive. To illustrate the importance of HMGB1 in this process, we confirmed that HMGB1 could be passive released by apoptotic β cells, not only by necrotic cells [6]. Defective clearance of apoptotic β cells may thereby results in the accumulation of extracellular HMGB1.…”

“…It has been suggested that HMGB1 is involved in the pathogenesis of multiple autoimmune diseases including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Experimental Allergic Encephalomyelitis (EAE) [4,5]. We recently demonstrated that HMGB1 is also implicated in the development of type 1 diabetes via activating innate immune response [5,6].…”

“…Using a spontaneous type 1 diabetes animal model (Non-Obese Diabetic mouse, NOD mouse), we demonstrated an essential role of HMGB1 in the development of type 1 diabetes [5,6]. Defects in apoptotic β cell clearance have been considered as an important cause of type 1 diabetes [20][21][22][23][24], although the underlying mechanisms remain elusive.…”

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

“…Wie bei anderen Autoimmunerkrankungen auch, kann HMGB1 dendritische zellen aktivieren und die Immunantwort gegen k ö rpereigene Betazellen lenken. Die Gabe von Anti-HMGB1-Antik ö rper konnten auch hier die Inzidenz reduzieren und den Krankheitsverlauf mildern [81,82] .…”