CD163 is a protein found on the surface of specific immune cells, particularly monocytes and macrophages. The “CD” in CD163 stands for “Cluster of Differentiation,” a standardized naming system for molecules on cell surfaces. These CD markers identify cell types and their roles within the immune system. CD163 functions as a receptor, binding to other molecules.
The Primary Role of CD163 in the Body
CD163 is predominantly expressed on monocytes and macrophages, white blood cells involved in the immune response. Its main physiological function involves acting as a scavenger receptor for the hemoglobin-haptoglobin complex. Hemoglobin, an oxygen-carrying protein in red blood cells, is released when red blood cells break down. Haptoglobin is a plasma protein that binds to free hemoglobin, forming a complex that CD163 recognizes and internalizes.
This process is comparable to a cellular cleanup crew removing debris. CD163 binds to these hemoglobin-haptoglobin complexes, facilitating their uptake into macrophages through endocytosis. Once inside the macrophage, the complex is degraded, and the iron from the hemoglobin can be recycled, preventing oxidative damage from free hemoglobin. This mechanism maintains iron balance and detoxifies free hemoglobin released during red blood cell turnover or increased red blood cell breakdown.
Function in Inflammation Control
Beyond clearing hemoglobin, CD163 is involved in regulating inflammatory responses. Macrophages are adaptable immune cells that differentiate into various subtypes. CD163 is a distinguishing marker for “M2” or “alternatively activated” macrophages.
These M2 macrophages are associated with anti-inflammatory functions, tissue repair, and inflammation resolution. They help calm the immune response after injury or infection, promoting healing and tissue remodeling. In contrast, “M1” macrophages are pro-inflammatory, initiating immune responses. The expression of CD163 on macrophages is influenced by anti-inflammatory signals, such as certain cytokines, highlighting its connection to dampening inflammation and fostering recovery.
The Soluble Form of CD163 as a Biomarker
CD163 also exists in a soluble form, known as soluble CD163 (sCD163). This form is generated when membrane-bound CD163 is shed or cleaved from macrophage surfaces. The shedding releases the receptor’s extracellular portion into the bloodstream.
Measuring sCD163 levels in the blood can serve as a biomarker, a measurable indicator of a biological state or condition. Elevated sCD163 levels indicate increased macrophage activation. This measurement provides insights into overall macrophage activity, especially in inflammatory processes.
CD163’s Involvement in Disease Processes
CD163’s functions, while beneficial in normal physiology, can contribute to disease progression when dysregulated. In cancer, CD163-expressing macrophages, termed Tumor-Associated Macrophages (TAMs), play a complex role within the tumor microenvironment. These TAMs can promote tumor growth by secreting factors that aid in tumor cell proliferation, migration, and invasion, and suppress the anti-cancer immune response. Increased numbers of CD163-positive TAMs have been linked to advanced stages of cancer and poorer patient outcomes.
In liver diseases, particularly those involving fibrosis and cirrhosis, elevated sCD163 levels are observed. This increase correlates with the severity of liver damage, reflecting heightened activity of macrophages, such as Kupffer cells, in inflamed and scarred liver tissue. High sCD163 levels can indicate ongoing inflammation and tissue remodeling processes contributing to liver pathology.
During severe infections, such as sepsis, widespread macrophage activation occurs. This leads to a significant increase in CD163 shedding, resulting in high sCD163 levels in the bloodstream. These elevated sCD163 concentrations are associated with infection severity and can correlate with poorer patient outcomes, serving as an indicator of systemic inflammation.
Targeting CD163 for Medical Treatment
Given CD163’s presence on macrophages involved in various diseases, researchers are exploring it as a target for therapies. One promising strategy involves developing antibody-drug conjugates (ADCs). These engineered molecules consist of an antibody that binds to CD163 on macrophages, linked to a therapeutic agent like a toxin or chemotherapy drug. This approach allows for precise delivery of the therapeutic agent directly to CD163-positive macrophages, minimizing off-target effects on healthy cells.
For example, in cancer, ADCs targeting CD163 can deliver anti-cancer drugs directly to tumor-associated macrophages, aiming to reprogram or eliminate these pro-tumor cells. Another therapeutic approach involves developing drugs that block CD163’s function to modify macrophage behavior or alter the microenvironment in inflammatory diseases or tumors. This could involve interfering with its scavenger receptor activity or signaling pathways to shift macrophages from a disease-promoting to a beneficial state.