Significance: The hemoglobin (Hb) scavenger receptor, CD163, is a macrophage-specific protein and the upregulated expression of this receptor is one of the major changes in the macrophage switch to alternative activated phenotypes in inflammation. Accordingly, a high CD163 expression in macrophages is a characteristic of tissues responding to inflammation. The scavenging of the oxidative and proinflammatory Hb leading to stimulation of the heme-oxygenase-1 and production of anti-inflammatory heme metabolites indicates that CD163 thereby indirectly contributes to the anti-inflammatory response. Recent Advances: In addition to this biological role in inflammation, CD163 is a potential inflammation biomarker and a therapeutic target. The biomarker form of CD163 is the soluble plasma CD163 that arises from the increased shedding of CD163 mediated by the tumor necrosis factor-α (TNF-α) cleaving enzyme. This explains that a steadily increasing literature documents that the plasma level of soluble CD163 is increased in a large spectrum of acute and chronic inflammatory disorders. The nonshed membrane form of CD163 in macrophages constitutes a target for drugs to be directed to macrophages in inflammation. This approach has been used in an animal inflammation model to highly increase the apparent therapeutic index of anti-inflammatory glucocorticoid drug that was coupled to an anti-CD163 antibody. Furthermore, other recent animal data, which indirectly involve CD163 in macrophages, demonstrate that injections of haptoglobin attenuate Hb-induced damages after blood transfusion. Critical Issues and Future Directions: The diagnostic and therapeutic properties of CD163 await further clinical studies and regulatory approval before implementation in the clinic. Antioxid. Redox Signal. 18, 2352–2363.

Heme released from heme-binding proteins on internal hemorrhage, hemolysis, myolysis, or other cell damage is highly toxic due to oxidative and proinflammatory effects. Complex formation with hemopexin, the high-affinity heme-binding protein in plasma and cerebrospinal fluid, dampens these effects and is suggested to facilitate cellular heme metabolism. Using a ligand-affinity approach, we purified the human hemopexin-heme receptor and identified it as the low-density lipoprotein receptor-related protein (LRP)/CD91, a receptor expressed in several cell types including macrophages, hepatocytes, neurons, and syncytiotrophoblasts. Binding experiments, including Biacore analysis, showed that hemopexin-heme complex formation elicits the high receptor affinity. Uptake studies of radio-labeled hemopexin-heme complex in LRP/CD91-expressing COS cells and confocal microscopy of the cellular processing of fluorescent hemopexin-heme complex established the ability of LRP/CD91 to mediate hemopexin-heme internalization resulting in cellular heme uptake and lysosomal hemopexin degradation. Uptake of hemopexin-heme complex induced LRP/CD91-dependent heme-oxygenase 1 mRNA transcription in cultured monocytes. In conclusion, hemopexin-heme complexes are removed by a receptor-mediated pathway showing striking similarities to the CD163-mediated haptoglobin-hemoglobin clearance in macrophages. Furthermore, the data indicate a hitherto unknown role of LRP/CD91 in inflammation. (Blood. 2005; 106:2572-2579)

CD163 is a hemoglobin scavenger receptor exclusively expressed in the monocyte‐macrophage system. A particularly high expression is seen in macrophages of the ‘alternative activation’ phenotype playing a major role in dampening the inflammatory response and in scavenging components of damaged cells. CD163‐mediated endocytosis of haptoglobin‐hemoglobin complexes formed upon red blood cell hemolysis leads to lysosomal degradation of the ligand protein and metabolism of heme by cytosolic heme oxygenase. In accordance with a stimulated expression of haptoglobin, CD163 and heme oxygenase‐1 during the acute phase response, there is evidence that this metabolic pathway regulates inflammation by at least two ways. First, CD163 is reported to directly induce intracellular signaling leading to secretion of anti‐inflammatory cytokines. Second and perhaps even more important, the CD163‐mediated delivery of hemoglobin to the macrophage may fuel an anti‐inflammatory response because heme metabolites have potent anti‐inflammatory effects. In addition to being present on the macrophage surface, continuous shedding of the extracellular domain of CD163 leads to substantial amounts of soluble receptor in plasma. An increased shedding is due to inflammatory stimuli, and a role for soluble CD163 in immune suppression has been proposed. Furthermore, recent data indicate that soluble CD163 may be a valuable diagnostic parameter for monitoring macrophage activation in inflammatory conditions.

Receptor-associated protein (RAP) is an endoplasmic reticulum/Golgi protein involved in the processing of receptors of the low density lipoprotein receptor family. A approximately 95-kDa membrane glycoprotein, designated gp95/sortilin, was purified from human brain extracts by RAP affinity chromatography and cloned in a human cDNA library. The gene maps to chromosome 1p and encodes an 833-amino acid type I receptor containing an N-terminal furin cleavage site immediately preceding the N terminus determined in the purified protein. Gp95/sortilin is expressed in several tissues including brain, spinal cord, and testis. Gp95/sortilin is not related to the low density lipoprotein receptor family but shows intriguing homologies to established sorting receptors: a 140-amino acid lumenal segment of sortilin representing a hitherto unrecognized type of extracellular module shows extensive homology to corresponding segments in each of the two lumenal domains of yeast Vps10p, and the extreme C terminus of the cytoplasmic tail of sortilin contains the casein kinase phosphorylation consensus site and an adjacent dileucine sorting motif that mediate assembly protein-1 binding and lysosomal sorting of the mannose-6-phosphate receptors. Expression of a chimeric receptor containing the cytoplasmic tail of gp95/sortilin demonstrates evidence that the tail conveys colocalization with the cation-independent mannose6-phosphate receptor in endosomes and the Golgi compartment.