First published December 20, 2018 - More info
Secreted by activated cells or passively released by damaged cells, extracellular HMGB1 is a prototypical damage-associated molecular pattern (DAMP) inflammatory mediator. During the course of developing extracorporeal approaches to treating injury and infection, we inadvertently discovered that haptoglobin, the acute phase protein that binds extracellular hemoglobin and targets cellular uptake through CD163, also binds HMGB1. Haptoglobin-HMGB1 complexes elicit the production of antiinflammatory enzymes (heme oxygenase-1) and cytokines (e.g., IL-10) in WT but not in CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 expression significantly enhances mortality rates in standardized models of intra-abdominal sepsis in mice. Administration of haptoglobin to WT and to haptoglobin gene-deficient animals confers significant protection. These findings reveal a mechanism for haptoglobin modulation of the inflammatory action of HMGB1, with significant implications for developing experimental strategies targeting HMGB1-dependent inflammatory diseases.
Huan Yang, Haichao Wang, Yaakov A. Levine, Manoj K. Gunasekaran, Yongjun Wang, Meghan Addorisio, Shu Zhu, Wei Li, Jianhua Li, Dominique P.V. de Kleijn, Peder S. Olofsson, H. Shaw Warren, Mingzhu He, Yousef Al-Abed, Jesse Roth, Daniel J. Antoine, Sangeeta S. Chavan, Ulf Andersson, Kevin J. Tracey
Original citation: JCI Insight. 2016;1(7):e85375. https://doi.org/10.1172/jci.insight.85375
Citation for this expression of concern: JCI Insight. 2018;3(24):e126616. https://doi.org/10.1172/jci.insight.126616
An investigative committee at the University of Liverpool recently identified concerns regarding the integrity of the NMR data contributed by Daniel J. Antoine for Figure 1, E and F, 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 Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes.