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 2

Protective role of haptoglobin in lethal sepsis.

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Protective role of haptoglobin in lethal sepsis. (A) Disruption of hapto...
(A) Disruption of haptoglobin expression renders mice more susceptible to lethal sepsis. Male WT (C57BL/6) and haptoglobin (Hp) KO mice (8–12 weeks old) were subjected to cecal ligation and puncture (CLP) surgery, and survival was monitored for 2 weeks (n = 15 mice per group). *P < 0.05 vs. WT group (Fisher’s exact test). (B) KO of Hp prolongs CLP-induced systemic accumulation of HMGB1 but not free hemoglobin. Male WT (C57BL/6) and Hp KO mice were subjected to CLP and euthanized at the indicated time points; serum-free hemoglobin and HMGB1 levels were measured. Data are from 3 (for day 21), 6 (for days 0, 2, and 14), and 7 (for day 7) mice at each time point. *P < 0.05, ***P < 0.001 vs. WT group (t test). (C and D) Administration of haptoglobin confers protection against sepsis lethality and reduces inflammation in WT and Hp KO mice. Upper: Male BALB/c or Hp KO mice were subjected to CLP surgery, and Hp was administered at 0.5 mg/mouse (for WT mice) or 0.2 mg/mouse (for Hp KO mice) in 200 μl volume, injected i.p. once a day for 3 days starting at 24 hours after CLP surgery. Mice in control group received vehicle (PBS) only. Survival was monitored for 2 weeks (n = 22 mice per group). *P < 0.05 vs. vehicle-treated group (Fisher’s exact test). Lower: Male WT (C57BL/6) or Hp KO mice were subjected to CLP surgery and received Hp (0.5 mg/mouse) or vehicle (PBS) i.p. at 24 and 36 hours after CLP surgery, and mice were euthanized at 48 hours after CLP. Sera were isolated for analyses. n = 7 (for WT group) and 8 (for Hp KO group) mice per group. *P < 0.05 vs. CLP-vehicle group (t test). (E) HMGB1-neutralizing antibodies confer protection against lethal sepsis in Hp KO mice. Hp KO mice (male, 8–12 weeks old) were subjected to CLP surgery, and neutralizing anti-HMGB1 mAbs or nonimmune mouse IgG were administered at 50 μg/mouse in 200 μl PBS, injected i.p. once a day for 3 days starting at 24 hours after CLP surgery. Survival was monitored for 2 weeks (n = 16 per group). *P < 0.05 vs. IgG control group (Fisher’s exact test).