First 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 corrigendum: J Clin Invest. https://doi.org/10.1172/JCI126975
The Editors posted an Expression of Concern for this article following notification that an investigative committee at the University of Liverpool had data integrity concerns regarding the mass spectrometry data contributed by Daniel J. Antoine for Supplemental Figure 6 of this paper. The authors have provided a corrected version of this article and a description of changes below.
In our published work, we reported that hepatocyte-derived HMGB1 triggers neutrophil-driven injury amplification following liver necrosis. We based our conclusions on extensive animal studies, including models of LPS-induced shock as well as models of hepatocyte apoptosis or necrosis in mice with cell-specific knockouts of HMGB1 and knockout of its main receptor, RAGE. Mice harboring bone marrow– and hepatocyte-specific deletion of HMGB1 showed vulnerability to endotoxemia and apoptotic liver injury equal to that of their wild-type littermates. However, in contrast to their floxed littermates, mice with hepatocyte-specific deletion of HMGB1 were protected from injury induced by acetaminophen intoxication or ischemia/reperfusion. While hepatocyte-specific HMGB1 deletion did not reduce initial injury in these models, it attenuated postnecrotic inflammation and neutrophil-mediated exacerbation of tissue damage. Accordingly, we found that these inflammatory and damage-exacerbating effects of HMGB1 were mediated by RAGE on bone marrow–derived cells, as demonstrated by studies in mice lacking neutrophil elastase in bone marrow and our finding that neutrophil migration required HMGB1 release from necrotic tissue and RAGE expression on neutrophils.
Supplemental Figure 6 shows data from an analysis of HMGB1 isoforms by mass spectrometry that was undertaken in a separate laboratory by Daniel J. Antoine. In September 2018, we learned that these data were compromised. We contacted the journal, and the Editorial Board agreed to publish an updated online version of the article. In the corrected version, all conclusions based on Supplemental Figure 6 have been removed, and the journal has published an online version of the original article and supplemental file with the unreliable statements and Supplemental Figure 6 crossed out (Supplemental File, Redaction) and the modified text highlighted in red. Daniel J. Antoine’s name was removed from the author list. The investigative committee at the University of Liverpool did not have any concerns in regard to the contributions and research activities of Rosalind E. Jenkins. Her name was removed from this publication solely because of a lack of contribution to the corrected manuscript. We affirm that the major conclusions of the study are accurate and that the corrected paper is reliable.
See the related article at The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis.