Regulation of the haptoglobin-hemoglobin scavenger receptor CD163 in the inflammatory response to endotoxin

Sepsis is a worldwide problem with an annual mortality rate reaching as high as 45%. Understanding its pathogenesis and the innate immune response to infection is key to the development of new treatments. CD163, a monocyte/macrophage-specific glycoprotein, is a receptor for haptoglobin-hemoglobin complexes. These complexes are rapidly formed in circulation following hemolysis of red blood cells during the acute inflammatory response. Previous work demonstrated that CD163 expression is influenced by elements of the acute inflammatory response. Work herein extended those studies to include endotoxin (LPS). One hour treatment of human monocytes with LPS induced metalloproteinase-mediated shedding of CD163, resulting in a soluble protein. In vivo administration of LPS to healthy volunteers demonstrated a rapid, highly reproducible rise in plasma CD163 levels by 2h. Surface CD163 expression was elevated by 24h. This rise is attributed to changes in circulating cytokine and hormone levels following LPS administration. Ligation of Toll-like receptors (TLR) 2 and 4 on human monocytes induced shedding of monocyte CD163 and inhibitors of LPS blocked TLR4-induced shedding. Further studies suggested that ligation of other TLR also produced the same effect on CD163 expression. The metalloproteinase inhibitor TAPI-0 prevented TLR-induced shedding of CD163, suggesting TLR ligation activates a common metalloproteinase that contributes to CD 163 shedding. Treatment of human monocytes with glucocorticoid (GC) and LPS significantly increased surface CD 163 expression, suggesting GC cross-talk as a mechanism for this effect. Upregulation of CD163 expression can be attributed in part, to new protein synthesis and resistance to shedding. Patients undergoing coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB) were used as an in vivo model to investigate CD163 regulation in response to an inflammatory stimulus. CABG patients have elevated plasma CD163 by one hour post declamping of the aorta (1h post DC) and increased monocyte surface CD163 by post-operative day 1 (POD1). GC administration prior to surgery significantly increased surface CD163 expression by POD1 but had no effect on plasma levels. These insights regarding regulation of both surface and soluble CD163 indicate that this molecule is an acute phase protein that is an important target for manipulation of the immune response to inflammatory stimuli and sepsis.