An immunogenic peptide in the A-box of HMGB1 protein reverses apoptosis-induced tolerance through RAGE receptor

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DOIResolve DOI: http://doi.org/10.1074/jbc.M113.541474
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TypeArticle
Journal titleJournal of Biological Chemistry
ISSN1083-351X
Volume289
Issue11
Pages77777786; # of pages: 10
SubjectBiochemistry; Biology; Advanced glycation end products; Apoptotic cells; Critically ills; DNA-binding domain; High-mobility groups; Immune tolerances; Inflammatory disease; Nosocomial infection; Cell death; advanced glycation end product; advanced glycation end product receptor; aspartic acid; cryopyrin; dendritic cell vaccine; high mobility group B1 protein; inflammasome; interleukin 1beta converting enzyme; recombinant enzyme; A box; active immunization; amino terminal sequence; animal cell; animal experiment; animal model; animal tissue; apoptosis; article; candidemia; cell therapy; delayed hypersensitivity; dendritic cell; DNA binding motif; embryo; immunogenicity; immunological tolerance; immunomodulation; in vitro study; mortality; mouse; nonhuman; priority journal; protein domain; protein protein interaction; secondary infection; sepsis; Apoptosis; Caspase; Inflammation; Innate Immunity; Receptor for Advanced Glycation End Products (RAGE); Sepsis; Tolerance; Animals; Apoptosis; Candida; Candidiasis; Caspase 1; Dendritic Cells; Fibroblasts; HMGB1 Protein; Immune Tolerance; Immunity, Innate; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptides; Receptors, Immunologic; Recombinant Proteins; Sepsis; Surface Plasmon Resonance
AbstractApoptotic cells trigger immune tolerance in engulfing phagocytes. This poorly understood process is believed to contribute to the severe immunosuppression and increased susceptibility to nosocomial infections observed in critically ill sepsis patients. Extracellular high mobility group box 1 (HMGB1) is an important mediator of both sepsis lethality and the induction of immune tolerance by apoptotic cells. We have found that HMGB1 is sensitive to processing by caspase-1, resulting in the production of a fragment within its N-terminal DNA-binding domain (the A-box) that signals through the receptor for advanced glycation end products (RAGE) to reverse apoptosis-induced tolerance. In a two-hit mouse model of sepsis, we show that tolerance to a secondary infection and its associated mortality were effectively reversed by active immunization with dendritic cells treated with HMGB1 or the Abox fragment, but not a noncleavable form of HMGB1. These findings represent a novel link between caspase-1 and HMGB1, with potential therapeutic implications in infectious and inflammatory diseases. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Biotechnology Research Institute (BRI-IRB)
Peer reviewedYes
NPARC number21272159
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Record identifier415c280e-d4c6-455f-9b20-e33489d951f2
Record created2014-07-23
Record modified2016-05-09
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