Published March 4, 2019 - More info
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.
Peter Huebener, Jean-Philippe Pradere, Celine Hernandez, Geum-Youn Gwak, Jorge Matias Caviglia, Xueru Mu, John D. Loike, Robert F. Schwabe
Original citation: J Clin Invest. 2015;125(2):539–550. https://doi.org/10.1172/JCI76887
Citation for this expression of concern: J Clin Invest. 2019;129(4):1802. https://doi.org/10.1172/JCI126976
An investigative committee at the University of Liverpool recently identified evidence of data fabrication relating to the mass spectrometry data contributed by Daniel J. Antoine for Supplemental Figure 6 of this paper. The Editorial Board is issuing this Expression of Concern to alert readers to this problem. No issues have been raised in regard to any of the other data in this manuscript.
See the related article at The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis.