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The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis
Peter Huebener, … , John D. Loike, Robert F. Schwabe
Peter Huebener, … , John D. Loike, Robert F. Schwabe
Published December 22, 2014
Citation Information: J Clin Invest. 2015;125(2):539-550. https://doi.org/10.1172/JCI76887.
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Research Article Hepatology Immunology Inflammation

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

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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

Peter Huebener, Jean-Philippe Pradere, Celine Hernandez, Geum-Youn Gwak, Jorge Matias Caviglia, Xueru Mu, John D. Loike, Robert F. Schwabe

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Figure 1

HMGB1 does not mediate LPS-induced inflammation and lethality.

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HMGB1 does not mediate LPS-induced inflammation and lethality.
Hmgb1fl/f...
Hmgb1fl/flMx1-Creneg and Hmgb1fl/fl Mx1-Crepos mice (Hmgb1del) (A–D) as well as Hmgb1fl/fl Vav1-Creneg and Hmgb1fl/fl Vav1-Crepos mice (Hmgb1ΔBM) (E and F) were treated with a lethal dose of LPS (80 mg/kg i.v.). (A–C) HMGB1 serum levels (A) (n = 4 per group), hepatic inflammatory gene expression (B), and serum chemokine levels (C) were determined in Hmgb1fl/fl and Hmgb1del (n = 7 per group) mice by ELISA and qPCR, respectively. (D) Survival was determined in Hmgb1fl/fl and Hmgb1del (n = 18 per group) mice. (E and F) Hmgb1fl/fl and Hmgb1ΔBM mice were treated with LPS (30 mg/kg). HMGB1 serum levels were determined 18 hours after LPS challenge (E) (n = 4 per group). Survival was determined in Hmgb1fl/fl and Hmgb1ΔBM mice (n = 12 per group). (G) Hmgb1fl/fl and Hmgb1ΔBM mice were treated with LPS (80 mg/kg). Survival was determined in Hmgb1fl/fl (n = 15) and Hmgb1ΔBM mice (n = 10). *P < 0.05, **P < 0.01, and ***P < 0.001 by 1-way ANOVA followed by Tukey’s multiple comparisons test (A, C, and E), unpaired 2-tailed t test (B), and Mantel-Cox log-rank test (D, F, and G), respectively. Un, untreated; ND, nondetectable; NS, nonsignificant.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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