Scavenger receptor cysteine-rich type 1 protein M130 (CD163) is a macrophage-specific receptor that plays a key role in clearing hemoglobin released during hemolysis and preventing the oxidation of heme iron. CD163 is a membrane receptor for the haptoglobin-hemoglobin (Hp-Hb) complex. The soluble form (sCD163) may have anti-inflammatory effects and is a valuable diagnostic parameter for monitoring macrophage activation under inflammatory conditions. It is involved in many diseases, including chronic inflammatory conditions such as atherosclerosis, asthma, and rheumatoid arthritis, as well as acute inflammatory disorders.
Expression distribution of CD163
CD163 is primarily expressed in macrophages and Kupffer cells, with a small amount present in circulating monocytes. CD163 expression is associated with the anti-inflammatory (M2) phenotype of macrophages, which participates in tissue repair and homeostasis.
Structure and ligands of CD163
CD163 is a 130 kDa type 1 transmembrane protein composed of nine consecutive cysteine-rich scavenger repeat (SRCR) domains, followed by a transmembrane segment and a short cytoplasmic tail that includes a functional internalization motif. Each SRCR domain is a compact globular structure of approximately 110 residues characterized by a highly conserved structure consisting of two β-sheets enclosing an α-helix . CD163 has three splice variants with different cytoplasmic tail lengths: two long tails and one short tail.
(Data source: Plevriti A, Lamprou M, Mourkogianni E, et al. Cells. 2024)
The trimeric structure of CD163 SRCR1-9 resembles an inverted tripod, with the ligand-binding regions (SRCR2-4) forming slender rod-like extensions that project into the extracellular space and enclose a cavity opposite the triangular base formed by CD163 SRCR5-9.
The trimeric assembly of CD163 subunits is promoted by specific intermolecular interactions. Each CD163 subunit uses its SRCR7 domain to bind to the SRCR9 domain of an adjacent CD163 molecule, and this interaction leads to the formation of a triangular base.
In CD163, potential calcium ions are located in SRCR2, SRCR3, SRCR6, SRCR7, and SRCR9, where calcium ions not only stabilize the conformation of the SRCR domain but also directly participate in ligand binding and oligomerization. For example, the calcium binding sites of SRCR2 and SRCR3 are crucial for ligand recognition.
(Data source: Etzerodt A, et al. Nat Commun. 2024)
Functions of CD163
Hemoglobin clearance: CD163 clears hemoglobin through endocytosis of the Hp-Hb complex, preventing oxidative damage caused by the iron in hemoglobin. This process is crucial for protecting tissues from oxidative stress. Free Hb can bind to CD163, leading to receptor-dependent endocytosis, which also inhibits Hp-Hb endocytosis, indicating the existence of a common binding site .
Anti-inflammatory effects: Macrophage expression of CD163 is associated with inflammation regulation. CD163 is a marker of macrophage activation. It protects monocytes from excessive activation during infections and inflammatory diseases by reducing the secretion of proinflammatory cytokines (such as TNF-a, IL-1β, IL-6, and IL-8). It also inhibits the production of proinflammatory chemokines, such as monocyte chemoattractant protein-1 (MCP-1), while promoting the secretion of anti-inflammatory mediators, such as IL-10.
with TWEAK: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, regulates multiple cellular processes , including inflammation, cell growth, angiogenesis, and apoptosis. CD163 clears the soluble form of TWEAK, while the receptor Fn14 targets its membrane form. CD163 binds to and internalizes sTWEAK, regulating NF-κB and Notch activation and promoting muscle regeneration. Studies have demonstrated that the TWEAK/Fn14/CD163 axis is involved in metabolic disorders, chronic autoimmune diseases, and acute ischemic stroke.
Regulation of the tumor microenvironment: In the tumor environment, CD163+ tumor-associated macrophages (TAMs) are often associated with poor prognosis. These macrophages promote tumor growth, angiogenesis, and immunosuppression by secreting pro-angiogenic and immunosuppressive factors such as vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and interleukin-10 (IL-10).
(Data source: Plevriti A, Lamprou M, Mourkogianni E, et al. Cells. 2024)
CD163-targeted therapy
Tetrachlorodecaoxide is a small molecule drug targeting CD163 that has been approved for marketing and is used to treat inflammation and allergic rhinitis.
Zovostotug (OR2805), developed by OncoResponse, is a humanized antibody targeting CD163 for the treatment of advanced malignant solid tumors. The antibody binds to CD163, which is highly expressed on tumor-associated macrophages (TAMs), creating an immunosuppressive tumor microenvironment and inhibiting anti-tumor T cell responses. NCT05094804 is a Phase 1 study investigating OR2805, a monoclonal antibody targeting CD163, alone and in combination with anticancer agents.
