CD163 - CD163 molecule |Elisa - Clia - Antibody - Protein

Background

CD163, also known as the hemoglobin scavenger receptor, is a transmembrane glycoprotein expressed primarily on the surface of monocytes and macrophages. Encoded by the CD163 gene on chromosome 12 in humans, CD163 functions as a receptor for the haptoglobin-hemoglobin (Hp-Hb) complex. It is critical in scavenging free hemoglobin (Hb) released during red blood cell breakdown, thus protecting tissues from oxidative damage and inflammation due to free hemoglobin. Additionally, CD163 is part of the cysteine-rich scavenger receptor family and plays an important role in immune modulation, inflammation resolution, and tissue remodeling.

Through its function as an anti-inflammatory receptor, CD163 contributes to the regulation of immune responses, often acting as a “sensor” for inflammatory conditions. When inflammation is detected, CD163-expressing cells can trigger responses that help protect tissues, making this molecule an essential component in maintaining immune homeostasis and limiting excessive immune reactions.

Protein Structure

CD163 is a large, complex protein composed of several important structural domains that facilitate its function:

Extracellular Domain:

• The extracellular region of CD163 is composed of nine scavenger receptor cysteine-rich (SRCR) domains, which provide binding sites for the haptoglobin-hemoglobin complex. These SRCR domains are characterized by their cysteine-rich sequences, which stabilize the extracellular region and enable specific binding with ligand molecules, such as haptoglobin-hemoglobin complexes and other plasma proteins.
• Glycosylation sites on the extracellular region contribute to the overall stability of CD163 and affect its ligand-binding properties. These post-translational modifications play a significant role in its interaction with binding partners and facilitate the anti-inflammatory response.

Transmembrane Domain:

• CD163 is anchored to the cell membrane through a single transmembrane helix that links the extracellular domains to the intracellular region. This anchoring allows CD163 to function as a receptor on the cell surface, facilitating ligand uptake into the macrophage or monocyte.

Cytoplasmic Tail:

• The short cytoplasmic tail of CD163 interacts with intracellular signaling molecules, mediating downstream responses following ligand binding. This intracellular region is essential for initiating endocytosis, a process in which CD163-ligand complexes are internalized into the cell for subsequent degradation and metabolism.
• Upon ligand engagement, signaling through the cytoplasmic tail leads to the release of anti-inflammatory cytokines and other mediators involved in immune response modulation.

Classification and Subtypes

CD163 is a member of the scavenger receptor family, specifically the scavenger receptor cysteine-rich (SRCR) family. While CD163 itself does not have distinct subtypes, it is sometimes referred to as CD163a to distinguish it from CD163b, which is an alternatively spliced form observed in certain studies but is less functionally characterized.

In terms of functional diversity, CD163 can be influenced by soluble forms:

• Soluble CD163 (sCD163): CD163 can be shed from the cell membrane by proteolytic cleavage, producing a soluble form (sCD163) found in plasma and other body fluids. This shedding is regulated by inflammatory stimuli, such as lipopolysaccharides (LPS) and cytokines. Elevated sCD163 levels are associated with various inflammatory and metabolic diseases, serving as a biomarker for immune activation.

Function and Biological Significance

CD163 plays essential roles in immune regulation and the resolution of inflammation through several key functions:

Hemoglobin Scavenging:

• The primary function of CD163 is to bind the haptoglobin-hemoglobin complex, which forms when free hemoglobin binds to haptoglobin in the bloodstream. This binding and internalization of the Hp-Hb complex into macrophages protect tissues from oxidative damage caused by free hemoglobin, thereby reducing inflammation and oxidative stress.
• After internalization, the Hp-Hb complex is degraded in lysosomes, releasing iron for recycling and producing anti-inflammatory heme metabolites that promote tissue repair.

Anti-inflammatory and Immunomodulatory Role:

• CD163 signaling activates anti-inflammatory pathways in macrophages, including the release of interleukin-10 (IL-10) and other anti-inflammatory cytokines, contributing to inflammation resolution.
• It is also involved in the production of heme oxygenase-1 (HO-1), an enzyme that metabolizes heme into biliverdin, carbon monoxide, and free iron, each of which has additional anti-inflammatory effects and promotes immune tolerance.

Pathogen Recognition and Clearance:

• CD163 can also recognize and bind to certain bacterial components, such as LPS. This function allows CD163 to act as a pathogen sensor, modulating the immune response to bacterial infections and endotoxins. During infections, CD163-positive macrophages help clear pathogens and promote an immune response tailored to neutralize the infectious agent.

Role in Tissue Repair and Remodeling:

• Through its anti-inflammatory and hemoglobin scavenging activities, CD163 plays a role in tissue repair following injury or infection. By producing anti-inflammatory cytokines, CD163-expressing cells contribute to a healing environment, helping to limit tissue damage and fibrosis.

Clinical Issues

Aberrant CD163 expression and function are associated with various inflammatory and metabolic diseases, as well as certain cancers:

Inflammatory and Metabolic Disorders:

• Elevated levels of soluble CD163 (sCD163) in the plasma are indicative of chronic inflammatory diseases, including rheumatoid arthritis, atherosclerosis, and type 2 diabetes. Increased sCD163 reflects macrophage activation in these conditions, often correlating with disease severity and progression.
• In obesity and metabolic syndrome, high sCD163 levels suggest ongoing low-grade inflammation driven by adipose tissue macrophages.

Infectious Diseases:

• CD163 expression is upregulated during infections, especially in response to bacterial components like LPS. This upregulation aids in pathogen clearance but can also result in excessive macrophage activation, contributing to immunopathology in diseases such as sepsis.

Cancer:

• Tumor-associated macrophages (TAMs) often exhibit high CD163 expression, promoting an immune-suppressive environment that favors tumor growth and progression. High levels of CD163-positive macrophages in the tumor microenvironment are associated with poorer outcomes in cancers such as breast, pancreatic, and ovarian cancers.

Hemolytic Disorders:

• Conditions that result in increased red blood cell breakdown, such as hemolytic anemia, sickle cell disease, and thalassemia, lead to elevated free hemoglobin levels in circulation. CD163 activity in these contexts is crucial to preventing oxidative damage; however, chronic engagement may deplete available CD163, leading to reduced scavenging capacity.

Biomarker Potential:

• sCD163 is used as a biomarker for macrophage activation and inflammation in several diseases. It is an indicator of disease activity in conditions such as HIV infection, liver fibrosis, and cardiovascular disease, providing insights into immune activation and prognosis.

Summary

CD163, the hemoglobin scavenger receptor, is a macrophage-expressed glycoprotein that plays a central role in immune modulation, inflammation resolution, and tissue protection. The structure of CD163 includes nine cysteine-rich extracellular domains crucial for ligand binding, a transmembrane domain, and a cytoplasmic tail that initiates endocytosis and intracellular signaling. CD163 scavenges free hemoglobin in the bloodstream by binding haptoglobin-hemoglobin complexes, preventing oxidative damage and inflammation. It also promotes anti-inflammatory responses through cytokine release and contributes to immune surveillance by recognizing bacterial components.

Clinically, CD163 is significant in several conditions, including inflammatory and metabolic disorders, infections, cancers, and hemolytic diseases. The soluble form, sCD163, serves as a valuable biomarker for macrophage activation in these conditions, providing insights into disease progression and immune status. Given its roles in immune regulation and inflammation resolution, CD163 remains a potential therapeutic target for modulating macrophage activity and addressing inflammation-associated diseases.