The CD163 marker is a protein found on the surface of specific immune cells, functioning as a scavenger receptor. It belongs to the scavenger receptor cysteine-rich (SRCR) family, which helps clear cellular debris and regulate the immune response. CD163 is primarily recognized as a marker of the monocyte and macrophage lineage. This protein plays a central role in inflammation by managing a toxic byproduct of red blood cell breakdown, helping maintain balance within the body’s tissues.
Cellular Residence and Structure
CD163 is predominantly expressed on the cell surface of monocytes and macrophages. Its expression is highest on mature, tissue-resident macrophages, such as Kupffer cells in the liver and red pulp macrophages in the spleen. These cells are specialized for clearing materials from circulation and within tissues.
The expression of CD163 is characteristic of the M2 macrophage phenotype, which is associated with anti-inflammatory responses, tissue repair, and wound healing. Anti-inflammatory mediators like glucocorticoids and interleukin-10 strongly induce CD163 expression on these cells. Conversely, pro-inflammatory signals tend to suppress its expression.
Structurally, CD163 is a single-chain transmembrane protein with a molecular size of about 130 kilodaltons. The protein spans the cell membrane, featuring a short intracellular tail and a large extracellular domain. This external portion consists of nine scavenger receptor cysteine-rich domains, which are responsible for binding to target molecules. This cell surface location allows CD163 to act as a receptor for molecules circulating in the bloodstream or present in the local tissue environment.
Primary Biological Function
The main function of membrane-bound CD163 is the clearance of a complex formed during red blood cell breakdown. When red blood cells are damaged, they release hemoglobin into the bloodstream, which is highly toxic and pro-oxidative if left unbound. The plasma protein haptoglobin immediately binds to this free hemoglobin, acting as the body’s first line of defense.
CD163 functions as the high-affinity scavenger receptor for the hemoglobin-haptoglobin complex. The receptor recognizes and binds the complex, initiating endocytosis to internalize the structure into the macrophage. This mechanism effectively removes the damaging free hemoglobin from circulation, preventing oxidative stress and inflammation in the blood vessel walls and tissues.
Once inside the macrophage, the complex is transported to the lysosomes for degradation. This process allows for the recycling of iron and the conversion of the toxic heme molecule into anti-inflammatory metabolites like carbon monoxide and biliverdin, catalyzed by the enzyme heme oxygenase-1. By removing and processing hemoglobin, CD163 contributes significantly to the resolution of inflammation and the maintenance of a protective, anti-inflammatory environment.
The Soluble Form
The membrane-bound CD163 can be cleaved from the macrophage surface and released into the bloodstream, resulting in soluble CD163 (sCD163). This process, called ectodomain shedding, occurs when specific enzymes, particularly metalloproteinases like ADAM17, cut the extracellular part of the protein near the cell membrane. The shedding of CD163 is stimulated by various inflammatory signals and is a direct consequence of macrophage activation.
The concentration of sCD163 in the blood is considered an indicator of generalized macrophage activation and the systemic inflammatory burden. While the precise biological function of the sCD163 molecule is not fully defined, it is thought that it may still bind to the hemoglobin-haptoglobin complex or act as a decoy receptor for other inflammatory molecules. The normal concentration of sCD163 in healthy individuals is generally low, ranging from approximately 0.7 to 3.9 milligrams per liter.
The half-life of sCD163 in the circulation is relatively long compared to other inflammatory markers, making it a long-term indicator of chronic activation. Since its release is triggered by inflammation, elevated levels serve as a measurable signal that the body’s macrophage system is broadly engaged in a response. This shedding mechanism provides a measurable link between the local activity of tissue macrophages and a patient’s systemic health status.
Clinical Significance in Disease
Measuring the level of sCD163 in the blood reflects the degree of macrophage activation across the body. Elevated sCD163 levels are associated with a wide spectrum of acute and chronic inflammatory disorders. This marker helps clinicians assess disease severity, monitor progression, and evaluate the effectiveness of treatment regimens.
In severe infections like sepsis, sCD163 levels are often elevated, and the concentration correlates with disease severity and patient outcome. High levels indicate activation of the macrophage population in response to the infection. sCD163 is also a biomarker in liver diseases, such as chronic viral hepatitis and non-alcoholic fatty liver disease, where the activation of resident liver macrophages (Kupffer cells) is a central feature.
sCD163 elevation is observed in chronic conditions, including chronic viral infections like HIV, autoimmune diseases, and cardiovascular disorders such as atherosclerosis. Its concentration correlates with the risk of developing type 2 diabetes, reflecting macrophage infiltration and inflammation in adipose tissue and the liver. High sCD163 and systemic inflammation make it a non-specific indicator of poor prognosis and comorbidity risk across various chronic health states.