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 Purohit, Zheng Dong, Mong Heng Wang, Jin Xiong She, Feili Gong, David 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
Externally publishedYes

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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

All Science Journal Classification (ASJC) codes

  • 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; Dong, Zheng; Wang, Mong Heng; She, Jin Xiong; Gong, Feili; Stern, David; Wang, Cong Yi.

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

Research output: Contribution to journalArticle

Han, J, Zhong, J, Wei, W, Wang, Y, Huang, Y, Yang, P, Purohit, S, Dong, Z, Wang, MH, She, JX, Gong, F, Stern, D & Wang, CY 2008, 'Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice', Diabetes, vol. 57, no. 8, pp. 2118-2127. https://doi.org/10.2337/db07-1499
Han, Junyan ; Zhong, Jinxin ; Wei, Wenzhong ; Wang, Ying ; Huang, Yafei ; Yang, Ping ; Purohit, Sharad ; Dong, Zheng ; Wang, Mong Heng ; She, Jin Xiong ; Gong, Feili ; Stern, David ; 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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title = "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 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 Sharad Purohit and Zheng Dong and Wang, {Mong Heng} and She, {Jin Xiong} and Feili Gong and David Stern 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

AU - Dong, Zheng

AU - Wang, Mong Heng

AU - She, Jin Xiong

AU - Gong, Feili

AU - Stern, David

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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