The Role of Soluble CD163 (sCD163) in Human Physiology and Pathophysiology

Abstract

Soluble CD163 (sCD163) is a circulating inflammatory mediator, indicative of acute and chronic, systemic and non-systemic inflammatory conditions. It is the cleavage outcome, consisting of almost the entire extracellular domain, of the CD163, a receptor expressed in monocytic lineages. Its expression is proportional to the abundance of CD163⁺ macrophages. Various mechanisms trigger the shedding of the CD163 receptor or the accumulation of CD163-expressing macrophages, inducing the sCD163 concentration in the circulation and bodily fluids. The activities of sCD163 range from hemoglobin (Hb) scavenging, macrophage marker, decoy receptor for cytokines, participation in immune defense mechanisms, and paracrine effects in various tissues, including the endothelium. It is an established marker of macrophage activation and thus participates in many diseases, including chronic inflammatory conditions, such as atherosclerosis, asthma, and rheumatoid arthritis; acute inflammatory conditions, such as sepsis, hepatitis, and malaria; insulin resistance; diabetes; and tumors. The sCD163 levels have been correlated with the severity, stage of the disease, and clinical outcome for many of these conditions. This review article summarizes the expression and role of sCD163 and its precursor protein, CD163, outlines the sCD163 generation mechanisms, the biological activities, and the known underlying molecular mechanisms, with an emphasis on its impact on the endothelium and its contribution in the pathophysiology of human diseases.

Keywords: CD163; cancer; endothelial cells; physiology; sCD163; soluble CD163.

Figure 1

Schematic representation of the three CD163 transmembrane isoforms. They differ in the length of the intracellular domains, with the 49-amino-acid isoform having dominant expression.

Figure 2

(A) Uniform manifold approximation and projection (UMAP) representation of all human cell types based on CD163 expression (data from 483,152 cells from the CZ database). (B) Clustering and analysis of the cell types with the highest CD163 expression.

Figure 3

Schematic representation of the hemoglobin clearance mechanism by CD163 in inflammatory conditions. The Hb released by the ruptured red cells is bound to the 3rd SRCR domain of the CD163 extracellular domain, either by itself or as a Hp–Hb complex, which eventually leads to CD163 internalization.

Figure 4

Schematic representation of sCD163 generation from the proteolytic cleavage of CD163. The list of the proteases known to cleave CD163 is shown on the left and the cleavage requires ATP consumption (black arrow).