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

Secreted by activated cells or passively released by damaged cells, extracellular HMGB1 functions as a pro-inflammatory mediator of infection or injury. It was previously unknown whether HMGB1 can be partner with other endogenous proteins to tilt the balance towards anti-inflammatory activities. Here we demonstrated that an acute phase protein, haptoglobin, effectively binds HMGB1, and triggers anti-inflammatory programs in a CD163-dependent fashion. Specifically, the HMGB1 and haptoglobin complexes elicit the production of anti-inflammatory enzymes (heme oxygenase-1) and cytokines (e.g., IL-10) in wild type, but not in CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 expression renders animals more susceptible to lethal sepsis, whereas administration of haptoglobin to wild type or to haptoglobin-gene deficient animals confers significant protection. These findings reveal a novel mechanism by which an acute phase protein modulates extracellular HMGB1 activities, and provides a novel strategy for treatment of HMGB1-dependent inflammatory diseases.