Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes
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
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
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Research Article Hepatology Immunology

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Abstract

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.

Authors

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

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Figure 4

Disruption of CD163 expression impairs haptoglobin-HMGB1 complex–induced IL-10 release and HO-1 expression and worsens CLP-induced sepsis.

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Disruption of CD163 expression impairs haptoglobin-HMGB1 complex–induced...
(A) KO of CD163 impairs haptoglobin-HMGB1–induced HO-1 expression and IL-10 release. Residential peritoneal macrophages from CD163 KO and WT (male C57BL/6) mice were stimulated with HMGB1 (1 μg/ml) alone or plus haptoglobin (3 μg/ml) for 16 hours. Extracellular levels of IL-10 and intracellular HO-1 expression levels were measured by ELISAs (n = 3 experiments). *P < 0.05, ***P < 0.001 vs. WT (t test). (B) Disruption of CD163 expression worsens lethal sepsis. WT (C57BL/6) or CD163 KO (male, 8–12 weeks of age) were subjected to CLP surgery, and survival was monitored for 2 weeks (n = 18 [WT] or 20 [CD163 KO] per group). *P < 0.05 vs. WT (Fisher’s exact test). (C) Deletion of CD163 sustains sepsis-induced elevation of circulating HMGB1 levels. WT (C57BL/6) and CD163 KO mice (male, 8–12 weeks old) were subjected to CLP and euthanized at indicated time points; serum HMGB1 and IL-6 levels were measured. n = 6 (for day 3), 7 (for days 0, 7, and 14), and 8 (for days 1 and 20) mice at each time point. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT group (t test).