| CD163 is a macrophage‑restricted transmembrane scavenger receptor of the class B scavenger receptor cysteine‑rich (SRCR) superfamily that is expressed on most mature tissue macrophages and serves as a key component of hemoglobin clearance and inflammatory regulation at blood–tissue interfaces. The extracellular region contains a tandem array of SRCR domains that bind hemoglobin–haptoglobin complexes with high affinity and mediate their endocytosis, which directs heme iron into intracellular degradation pathways and limits oxidative and proinflammatory effects of extracellular hemoglobin. The same SRCR architecture recognizes native and chemically modified hemoglobins in the absence of haptoglobin and supports interactions with developing erythroblasts in erythroblastic islands, assigning CD163 a role in both erythrocyte turnover and erythropoietic niches. CD163 also functions as an innate immune sensor, since its ectodomain binds both Gram‑positive and Gram‑negative bacteria and transduces signals that enhance proinflammatory cytokine production by macrophages, coupling pattern recognition with local inflammatory mediator release. Expression of CD163 is tightly regulated by the cytokine milieu, with anti‑inflammatory mediators such as IL‑10 and glucocorticoids, and IL‑6 in specific contexts, inducing or upregulating CD163, whereas proinflammatory cytokines including TNF reduce its surface expression, aligning CD163 positivity with alternatively activated, anti‑inflammatory macrophage phenotypes. Engagement of CD163 by hemoglobin–haptoglobin complexes or antibody‑mediated cross‑linking activates intracellular signaling pathways that include tyrosine kinase and calcium‑dependent components and lead to the production of anti‑inflammatory cytokines such as IL‑10 as well as modulation of IL‑6 secretion, which integrates CD163 into feedback loops that resolve inflammation. Proteolytic cleavage of the extracellular domain generates soluble CD163 (sCD163) that retains all SRCR domains, circulates in blood, and supports uptake of free hemoglobin; ligands of Toll‑like receptors 2, 4, and 5, as well as other inflammatory triggers, enhance ectodomain shedding and increase sCD163 levels during systemic and local inflammation. Serum sCD163 concentrations rise in a broad spectrum of inflammatory, infectious, and metabolic diseases and correlate with disease activity and severity, which makes sCD163 a useful biomarker for diagnosis, prognosis, and therapy monitoring in conditions such as sepsis, chronic liver disease, autoimmune disorders, and some malignancies. High CD163 expression marks macrophage subsets with immunomodulatory and tissue‑repair profiles and is widely used to identify M2‑like macrophages in tissues, including tumor‑associated macrophages, where CD163 positivity aligns with microenvironments characterized by immunosuppression and active remodeling. |
