CD163 and inflammation: biological, diagnostic, and therapeutic aspects

Abstract

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.

FIG. 1.

Scavenger receptor cysteine-rich (SRCR) class B family membrane protein members. All members contain multiple extracellular repeats of the SRCR class B domain. A conserved repeat, known as the long-range cassette, is defined by a cassette of five SRCR domains separated by a 31 amino acid spacer between repeat 2 and 3. All the proteins, except for WC1, which was identified in the pig, are encoded by the human genome. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.

FIG. 2.

CD163-mediated scavenging of Hb upon intravascular hemolysis. CD163 is highly expressed on phagocytic macrophages. Upon hemolysis, released hemoglobin (Hb) is rapidly bound by the acute-phase protein Hp forming the haptoglobin–hemoglobin (Hp-Hb) complex. The complex is subsequently bound and removed from the circulation by CD163-positive macrophages in the liver, spleen,and bone marrow. The uptake of Hb by macrophages contributes to the recycling of iron and also to the inflammatory response. The uptake of Hb in macrophages and subsequent degradation of heme by heme oxygenase-1 (HO-1), produce the anti-inflammatory metabolites, Fe²⁺, CO, and biliverdin. Biliverdin reductase converts biliverdin to bilirubin, which is secreted to the cell exterior. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.

FIG. 3.

A disintegrin and metalloproteinase 17 (ADAM17)/tumor necrosis factor (TNF)-α converting enzyme (TACE)-mediated shedding of CD163 and TNF-α upon stimulation by proinflammatory stimuli. CD163 and proTNF-α are rapidly cleaved from the surface of activated macrophages by an ADAM17/TACE-dependent mechanism. A number of proinflammatory substances induce ADAM17/TACE activation. The exact site of cleavage in CD163 awaits identification. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.

FIG. 4.

Soluble CD163 is a long-circulating surrogate marker of TNF-α in experimental endotoxemia. Serum levels of sCD163 and TNF-α in healthy volunteers (n=8) after receiving a bolus-injection of endotoxin. Serum analysis shows a fast increase in both markers, whereas TNF-α rapidly cleared increased levels sCD163 are still measured after 24 h. The figure is reproduced from (28) with permission from J. Leuk. Biology.

FIG. 5.

Using CD163 as a target for directed drug delivery. The endocytic property of CD163 allows either ligand- or antibody-associated drugs to have an easy and specific access to cytosolic compartment of macrophages. The figure shows examples of two types of conjugates: CD163 antibody- or ligand-drug conjugates and drugs encapsulated in pegylated liposomes with a CD163-binding antibody or ligand linked to the phospholipid layer. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.