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.
  
  
  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 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-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.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Department of Pathology, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Junyan
authors.initials: J
authors.lastname: Han
authors.forename: Jinxin
authors.initials: J
authors.lastname: Zhong
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Wei
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yafei
authors.initials: Y
authors.lastname: Huang
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Sharad
authors.initials: S
authors.lastname: Purohit
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
authors.forename: Feili
authors.initials: F
authors.lastname: Gong
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015551:Autoimmunity / Q000276:immunology; D015153:Blotting, Western; D039521:CD11c Antigen / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000906:Antibodies; D039521:CD11c Antigen; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D024243:HMGB1 Protein; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma