Hemoglobin Scavenger Receptor CD163 Mediates Interleukin-10 Release and Heme Oxygenase-1 Synthesis

Abstract

Abstract-The recently described hemoglobin scavenger receptor CD163 mediates the endocytosis of hemoglobin:haptoglobin (Hb:Hp) complexes and thereby counters Hb-induced oxidative tissue damage after hemolysis. Although CD163 has been indirectly associated with antiinflammatory and atheroprotective activity, no ligand-receptor-effector pathway has yet been described for this receptor. To understand the significance of CD163 and more clearly define downstream pathways linked to inflammatory resolution, we studied the expression and function of CD163 in human monocytes/macrophages using both in vitro and in vivo models. Differentiation of human blood monocytes into macrophages either by in vitro culture or in resolving cantharidin-induced skin blisters led to an equivalent increase (Ͼ15ϫ) in CD163 expression. Elevated CD163 levels were also noted on circulating monocytes in cardiac surgical patients during the resolution phase of the systemic inflammatory response to cardiopulmonary bypass surgery. In each case, binding of Hb:Hp to CD163-bearing cells elicited potent interleukin-10 secretion, and this was inhibited by the anti-CD163 antibody RM3/1. Release of interleukin-10, in turn, induced heme oxygenase-1 stress protein synthesis via an autocrine mechanism. Such induction of heme oxygenase-1 was observed in vivo 24 to 48 hours after the onset of cardiopulmonary bypass surgery. These results identify novel antiinflammatory and cytoprotective effector pathways in human monocytes/macrophages related to Hb scavenging and metabolism, which may have relevance in atheroprotection, wound healing, and patient recovery postoperatively.

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…The latter is suppressed with blocking antibodies for the CD163 receptor or soluble antibodies to IL-10. This finding, which was recapitulated in macrophages isolated from skin blisters and patients on cardiopulmonary bypass, suggests that IL-10 represents a link between increased ability for clearance of Hb during inflammation and the induction of HO-1 in MM (133).…”

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…Among them, only expression of CD206 (a marker for M2 polarization [40]) demonstrated differential regulation by LPS and MSCs; MDM expression of CD206 was significantly increased by MSCs in both the presence (40 6 16% increase) and the absence (25 6 12% increase) of LPS ( Figure 1C). Notably, expression of CD163 (an established M2 marker [41]), although detectable, was not affected by any of the stimulations. MSCs significantly increased the proportion of phagocytic MDMs in the presence of LPS by 2.9-fold compared with LPS alone ( Figure 1D).…”

Macrophages of genetically characterized familial hypercholesterolaemia patients show up‐regulation of LDL‐receptor‐related proteins

“…We have also shown that a higher number of monocytes differentiate towards a CD16 + phenotype in the presence of native LDL 49. Macrophages CD16 + are usually related to a mature M2‐phenotype, also characterized for being positive for CD163 20 a scavenger receptor of the haemoglobin–haptoglobin complex involved in haeme catabolism through a process mediated by regulation of the haeme oxygenase‐1 (HMOX1) expression 79. The presence of CD163 macrophages in human atherosclerotic lesions has been also associated with anti‐inflammatory properties mediated through IL10 21, and studies in mice ApoE −/− models have associated plaque regression with the presence of M2 macrophage expressing CD163 80, 81, 82.…”