The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis

Peter Huebener, Jean-Philippe Pradere, Celine Hernandez, Geum-Youn Gwak, Jorge Matias Caviglia, Xueru Mu, John D Loike, Rosalind E Jenkins, Daniel J Antoine, Robert F Schwabe

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)539-50
Number of pages12
JournalJournal of Clinical Investigation
Issue number2
Publication statusPublished - Feb 2015

Keywords / Materials (for Non-textual outputs)

  • Acetaminophen
  • Analgesics, Non-Narcotic
  • Animals
  • Chemical and Drug Induced Liver Injury
  • HMGB1 Protein
  • Hepatocytes
  • Inflammation
  • Leukocyte Elastase
  • Lipopolysaccharides
  • Macrophages
  • Mice
  • Mice, Knockout
  • Necrosis
  • Neutrophil Infiltration
  • Neutrophils
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Shock, Septic
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Journal Article
  • Research Support, N.I.H., Extramural


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