CD163 Human

What is CD163 and what are its primary functions in humans?

CD163 (Cluster of Differentiation 163) is a 130 kDa protein exclusively expressed on cells of the monocyte/macrophage lineage in humans. It functions primarily as a high-affinity scavenger receptor for the hemoglobin-haptoglobin complex and, with lower affinity, for hemoglobin alone in the absence of haptoglobin . The receptor was first discovered in 1987 and has since been recognized as an important innate immune sensor for both gram-positive and gram-negative bacteria . CD163 serves as a definitive marker for identifying macrophages in tissue samples and plays a crucial role in the resolution phase of inflammation .

In everyday physiology, CD163 neutralizes pro-oxidant free heme released during hemolysis in bruising or tissue injury . During inflammatory resolution, CD163-expressing macrophages engulf apoptotic neutrophils, contributing to wound healing and tissue regeneration . This transition to CD163+ macrophages represents a key switching point from the cytodestructive inflammatory phase to the resolving phase supporting tissue repair .

What is the molecular structure of human CD163?

Human CD163 belongs to the scavenger receptor cysteine-rich (SRCR) family type B with a molecular size of 130 kDa . Its structure consists of:

• A 1048 amino acid residue extracellular domain

• A single transmembrane segment

• A cytoplasmic tail with several splice variants

The extracellular portion contains nine SRCR domains (numbered 1-9), which play different roles in ligand binding and recognition . These domains have been studied using various domain-specific monoclonal antibodies recognizing epitopes in SRCR domains 1, 4, 7, and 9 . The structural arrangement of these domains contributes to CD163's specialized functions in hemoglobin-haptoglobin complex binding and bacterial sensing.

How does soluble CD163 (sCD163) relate to membrane-bound CD163?

A soluble form of CD163, commonly denoted as sCD163, exists in plasma and cerebrospinal fluid . This soluble variant is generated through ectodomain shedding of the membrane-bound receptor, which occurs as a result of enzymatic cleavage by ADAM17 (a disintegrin and metalloproteinase 17) . This shedding process may represent a form of modulation of CD163 function .

sCD163 serves as a valuable biomarker in various inflammatory conditions. Its levels are significantly upregulated in a range of diseases including liver cirrhosis, type 2 diabetes, macrophage activation syndrome, Gaucher's disease, sepsis, HIV infection, rheumatoid arthritis, and Hodgkin lymphoma . Additionally, elevated sCD163 in cerebrospinal fluid is observed after subarachnoid hemorrhage, and its urinary excretion tightly correlates with active glomerulonephritis in systemic lupus erythematosus and ANCA vasculitis, potentially allowing clinicians to track therapeutic responses .

Why do studies report such variable levels of CD163 expression on human monocytes?

A significant challenge in CD163 research has been the wide discrepancy in reported percentages of CD163-expressing blood monocytes in healthy individuals . This inconsistency stems primarily from two factors:

• Epitope accessibility: The measured proportion of CD163-expressing monocytes increases significantly when using CD163 monoclonal antibodies that recognize epitopes in the N-terminal part of CD163, remote from the membrane surface . Antibodies targeting different domains yield substantially different results.

• Calcium dependency: The proportion of CD163-positive monocytes observed is highly dependent on free calcium levels . Some antibodies exhibit altered binding characteristics in the presence or absence of calcium, affecting detection rates.

In carefully controlled studies using antibodies directed at the N-terminal part of CD163 (specifically SRCR domain 1), consistently more than 80% of monocytes in human peripheral blood were identified as CD163-positive . This suggests that most, and potentially all, human peripheral blood monocytes express CD163, but detection varies based on methodological approaches.

Which antibodies are most effective for detecting CD163 in human samples?

Research has characterized several domain-specific CD163 monoclonal antibodies that recognize different SRCR domains, each with unique binding properties:

For researchers seeking the most accurate assessment of CD163 expression, antibodies targeting the N-terminal SRCR domain 1 (like MAC2-158) are recommended as they consistently identify the highest percentage of CD163-positive monocytes and are less affected by calcium levels .

How can CD163 be used to track macrophage phenotype evolution during inflammation?

The cantharidin skin blister model provides an excellent approach for tracking macrophage phenotype changes during inflammation resolution in humans . This two-day model effectively discriminates between the inflammatory and resolving phases:

• Inflammatory phase (16 hours): Characterized by predominantly CD14+ monocytes without CD163 expression and elevated pro-inflammatory cytokines .

• Resolving phase (40 hours): Marked by the appearance of CD14+CD163+ "resolving macrophage" phenotype, coinciding with neutrophil apoptosis and phagocytosis by macrophagic "Reiter's" cells .

This transition correlates with a shift in cytokine profiles:

By tracking the emergence of the CD163+ phenotype and correlating it with cytokine profile changes, researchers can effectively monitor the switch from pro-inflammatory to resolving phases in various inflammatory models .

What are the critical differences between human and mouse CD163 that impact translational research?

Researchers conducting preclinical studies in mice should be aware of significant species differences in CD163 biology:

These differences highlight potential limitations in using mouse models to study CD163-mediated processes that might be relevant to human diseases . Researchers should carefully consider these species-specific variations when designing translational studies and interpreting results.

How does CD163 contribute to disease pathophysiology?

CD163 plays significant roles in various disease processes:

• Inflammatory diseases: The soluble form (sCD163) serves as a biomarker for disease activity in numerous inflammatory conditions. Its elevation correlates with disease severity in conditions ranging from liver cirrhosis to HIV infection .

• Neurodegenerative conditions: CD163 has been identified as expressed on neurons in the CNS following hemorrhage, although the significance remains unclear .

• Cardiovascular disease: In atherosclerotic plaques, CD163+ macrophages help dampen oxidative injury due to intraplaque hemorrhage .

• Autoimmune diseases: Urinary sCD163 serves as a biomarker for active glomerulonephritis in systemic lupus erythematosus and ANCA vasculitis, allowing clinicians to track response to therapy .

• Infection resistance: Animal studies have shown that gene modifications affecting CD163 can confer resistance to certain viral infections. For example, pigs with a section of the CD163 gene removed demonstrated complete resistance to the virus causing Porcine Reproductive and Respiratory Syndrome .

What methodological approaches best characterize CD163+ macrophage functions in human tissue samples?

When investigating CD163+ macrophage functions in human tissues, researchers should consider:

• Flow cytometry: Using N-terminal-directed antibodies (particularly domain 1) for most consistent detection . Consider calcium dependency when selecting antibodies.

• Inflammatory phase discrimination: The cantharidin skin blister model effectively discriminates inflammatory phases within a two-day timeframe, providing a powerful research tool for clinical settings .

• Cytokine profiling: Monitoring the shift from pro-inflammatory (MCP-1, IL-6, IL-8) to immunoregulatory cytokines (TGF-α, MDC, IP-10) can help confirm the functional transition to CD163+ resolving macrophages .

• Phagocytosis assays: Evaluating the phagocytic capacity of CD163+ macrophages, particularly toward apoptotic neutrophils, confirms their role in inflammation resolution .

• Combined markers: Assessment of CD14+CD163+ double-positive cells provides more specific identification of resolving macrophage phenotypes than either marker alone .

How might CD163 be exploited as a therapeutic target?

Given its role in inflammation resolution and specific expression on monocyte/macrophage lineage cells, CD163 represents a potential therapeutic target for various inflammatory conditions . Future research directions might include:

• Developing strategies to enhance CD163 expression to promote inflammation resolution

• Targeting the CD163 pathway to modulate macrophage phenotype in chronic inflammatory diseases

• Using CD163 as a delivery mechanism for macrophage-targeted therapies

• Exploring the potential of sCD163 as a biomarker for therapeutic response in clinical trials

What are the knowledge gaps regarding CD163 regulation during disease states?

Despite extensive research, several questions remain regarding CD163 biology:

• The precise mechanisms controlling the switch from CD163- to CD163+ macrophage phenotype during inflammation resolution

• The functional significance of CD163 expression on neurons following CNS hemorrhage

• The complete signaling pathways activated by CD163 engagement in human macrophages

• The relationship between genetic variants of CD163 and disease susceptibility or progression

• The clinical significance of different splice variants in the cytoplasmic tail