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

Hdl Handle:
http://hdl.handle.net/10675.2/17
Title:
Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice.
Authors:
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 M.; Wang, Cong-Yi
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 beta-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 na??ve 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-gamma(+) (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.
Citation:
Diabetes. 2008 Aug; 57(8):2118-2127
Issue Date:
29-Jul-2008
URI:
http://hdl.handle.net/10675.2/17
DOI:
10.2337/db07-1499
PubMed ID:
18477810
PubMed Central ID:
PMC2494682
Type:
Journal Article; Research Support, Non-U.S. Gov't
ISSN:
1939-327X
Appears in Collections:
Center for Biotechnology and Genomic Medicine: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorHan, Junyanen_US
dc.contributor.authorZhong, Jinxinen_US
dc.contributor.authorWei, Wenzhongen_US
dc.contributor.authorWang, Yingen_US
dc.contributor.authorHuang, Yafeien_US
dc.contributor.authorYang, Pingen_US
dc.contributor.authorPurohit, Sharaden_US
dc.contributor.authorDong, Zhengen_US
dc.contributor.authorWang, Mong-Hengen_US
dc.contributor.authorShe, Jin-Xiongen_US
dc.contributor.authorGong, Feilien_US
dc.contributor.authorStern, David M.en_US
dc.contributor.authorWang, Cong-Yien_US
dc.date.accessioned2010-09-24T20:59:20Z-
dc.date.available2010-09-24T20:59:20Z-
dc.date.issued2008-07-29en_US
dc.identifier.citationDiabetes. 2008 Aug; 57(8):2118-2127en_US
dc.identifier.issn1939-327Xen_US
dc.identifier.pmid18477810en_US
dc.identifier.doi10.2337/db07-1499en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/17-
dc.description.abstractOBJECTIVE: 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 beta-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 na??ve 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-gamma(+) (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.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntibodies / immunology / pharmacologyen_US
dc.subject.meshAntigens, CD11c / immunologyen_US
dc.subject.meshAntigens, CD8 / immunologyen_US
dc.subject.meshAutoimmunity / immunologyen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshCD8-Positive T-Lymphocytes / drug effects / immunologyen_US
dc.subject.meshCell Lineen_US
dc.subject.meshCell Survival / drug effectsen_US
dc.subject.meshDendritic Cells / drug effects / immunology / metabolismen_US
dc.subject.meshDiabetes Mellitus, Type 1 / immunology / pathology / prevention & controlen_US
dc.subject.meshEnzyme-Linked Immunosorbent Assayen_US
dc.subject.meshFlow Cytometryen_US
dc.subject.meshForkhead Transcription Factors / metabolismen_US
dc.subject.meshHMGB1 Protein / genetics / immunology / metabolismen_US
dc.subject.meshImmunity, Innate / immunologyen_US
dc.subject.meshInsulin-Secreting Cells / cytology / drug effects / metabolismen_US
dc.subject.meshInterferon-gamma / metabolismen_US
dc.subject.meshMacrophages / cytology / drug effects / metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred C57BLen_US
dc.subject.meshMice, Inbred NODen_US
dc.subject.meshRecombinant Proteins / pharmacologyen_US
dc.subject.meshTumor Necrosis Factor-alpha / metabolismen_US
dc.titleExtracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.identifier.pmcidPMC2494682en_US
dc.contributor.corporatenameCenter for Biotechnology and Genomic Medicineen_US
dc.contributor.corporatenameDepartment of Pathologyen_US
dc.contributor.corporatenameDepartment of Cellular Biology and Anatomyen_US
dc.contributor.corporatenameDepartment of Physiologyen_US
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