Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes.
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.
Laboratories of Biomedical Science and.
Huan
H
Yang
Emergency Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
Haichao
H
Wang
Laboratories of Biomedical Science and.
Yaakov A
YA
Levine
Laboratories of Biomedical Science and.
Manoj K
MK
Gunasekaran
Laboratories of Biomedical Science and.
Yongjun
Y
Wang
Laboratories of Biomedical Science and.
Meghan
M
Addorisio
Emergency Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
Shu
S
Zhu
Emergency Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
Wei
W
Li
Laboratories of Biomedical Science and.
Jianhua
J
Li
Laboratory of Cardiovascular Immunology, University Medical Center, Utrecht, Netherlands.
Dominique Pv
DP
de Kleijn
Laboratories of Biomedical Science and.
Peder S
PS
Olofsson
Infectious Disease Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
H Shaw
HS
Warren
Laboratories of Medicinal Chemistry and.
Mingzhu
M
He
Laboratories of Medicinal Chemistry and.
Yousef
Y
Al-Abed
Diabetes and Diabetes-related Disorders, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
Jesse
J
Roth
MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Daniel J
DJ
Antoine
Laboratories of Biomedical Science and.
Sangeeta S
SS
Chavan
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Ulf
U
Andersson
Laboratories of Biomedical Science and.
Kevin J
KJ
Tracey