Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice

Junyan Han, Jinxin Zhong, Wenzhong Wei, Ying Wang, Yafei Huang, Ping Yang, Sharad B Purohit, Zheng Dong, Mong-Heng Wang, Jin-Xiong She, Feili Gong, David M. Stern, Cong Yi Wang

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)2118-2127
Number of pages10
JournalDiabetes
Volume57
Issue number8
DOIs
StatePublished - Aug 1 2008

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Inbred NOD Mouse
Type 1 Diabetes Mellitus
Dendritic Cells
Autoimmunity
T-Lymphocytes
Lymph Nodes
Macrophage Activation
Regulatory T-Lymphocytes
Neutralizing Antibodies
Islets of Langerhans
Innate Immunity
Interferons
Research Design
Spleen
Cell Count
Antibodies
Proteins

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice. / Han, Junyan; Zhong, Jinxin; Wei, Wenzhong; Wang, Ying; Huang, Yafei; Yang, Ping; Purohit, Sharad B; Dong, Zheng; Wang, Mong-Heng; She, Jin-Xiong; Gong, Feili; Stern, David M.; Wang, Cong Yi.

In: Diabetes, Vol. 57, No. 8, 01.08.2008, p. 2118-2127.

Research output: Contribution to journalArticle

Han, Junyan ; Zhong, Jinxin ; Wei, Wenzhong ; Wang, Ying ; Huang, Yafei ; Yang, Ping ; Purohit, Sharad B ; Dong, Zheng ; Wang, Mong-Heng ; She, Jin-Xiong ; Gong, Feili ; Stern, David M. ; Wang, Cong Yi. / Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice. In: Diabetes. 2008 ; Vol. 57, No. 8. pp. 2118-2127.
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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.",
author = "Junyan Han and Jinxin Zhong and Wenzhong Wei and Ying Wang and Yafei Huang and Ping Yang and Purohit, {Sharad B} and Zheng Dong and Mong-Heng Wang and Jin-Xiong She and Feili Gong and Stern, {David M.} and Wang, {Cong Yi}",
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T1 - Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice

AU - Han, Junyan

AU - Zhong, Jinxin

AU - Wei, Wenzhong

AU - Wang, Ying

AU - Huang, Yafei

AU - Yang, Ping

AU - Purohit, Sharad B

AU - Dong, Zheng

AU - Wang, Mong-Heng

AU - She, Jin-Xiong

AU - Gong, Feili

AU - Stern, David M.

AU - Wang, Cong Yi

PY - 2008/8/1

Y1 - 2008/8/1

N2 - 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.

AB - 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.

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