title: The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis.
abstract: In contrast to microbially triggered inflammation, mechanisms promoting sterile inflammation remain poorly understood. Damage-associated molecular patterns (DAMPs) are considered key inducers of sterile inflammation following cell death, but the relative contribution of specific DAMPs, including high-mobility group box 1 (HMGB1), is ill defined. Due to the postnatal lethality of Hmgb1-knockout mice, the role of HMGB1 in sterile inflammation and disease processes in vivo remains controversial. Here, using conditional ablation strategies, we have demonstrated that epithelial, but not bone marrow-derived, HMGB1 is required for sterile inflammation following injury. Epithelial HMGB1, through its receptor RAGE, triggered recruitment of neutrophils, but not macrophages, toward necrosis. In clinically relevant models of necrosis, HMGB1/RAGE-induced neutrophil recruitment mediated subsequent amplification of injury, depending on the presence of neutrophil elastase. Notably, hepatocyte-specific HMGB1 ablation resulted in 100% survival following lethal acetaminophen intoxication. In contrast to necrosis, HMGB1 ablation did not alter inflammation or mortality in response to TNF- or FAS-mediated apoptosis. In LPS-induced shock, in which HMGB1 was considered a key mediator, HMGB1 ablation did not ameliorate inflammation or lethality, despite efficient reduction of HMGB1 serum levels. Our study establishes HMGB1 as a bona fide and targetable DAMP that selectively triggers a neutrophil-mediated injury amplification loop in the setting of necrosis.
authors.forename: Peter
authors.initials: P
authors.lastname: Huebener
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pradere
authors.forename: Celine
authors.initials: C
authors.lastname: Hernandez
authors.forename: Geum-Youn
authors.initials: GY
authors.lastname: Gwak
authors.forename: Jorge Matias
authors.initials: JM
authors.lastname: Caviglia
authors.forename: Xueru
authors.initials: X
authors.lastname: Mu
authors.forename: John D
authors.initials: JD
authors.lastname: Loike
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; C491899:Fas protein, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000082:Acetaminophen; D019272:Leukocyte Elastase