What Are GPNMB Macrophages and What Is Their Function?

Within the human body, a specific relationship exists between a protein and an immune cell. Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) is a protein found in various cells, while macrophages are a fundamental component of the immune system. The expression of GPNMB in macrophages creates a specialized cell with distinct functions, playing roles in both maintaining health and responding to disease.

Defining GPNMB and Macrophages

Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) is a transmembrane glycoprotein, meaning it passes through the cell membrane. Although first identified in melanoma cells, it is also present in normal cell types like bone and skin cells. Its structure allows it to be cleaved, releasing a soluble fragment that can signal to other cells.

Macrophages are white blood cells that originate from monocytes. When monocytes move from the bloodstream into tissues, they become macrophages, a name meaning “big eaters.” This reflects their primary function of phagocytosis: engulfing cellular debris, pathogens, and cancer cells. Macrophages also signal other immune cells to help coordinate an immune response.

Not all macrophages express GPNMB. Its presence is induced by specific signals within the body, particularly in environments of inflammation or tissue injury. This inducibility means that GPNMB-expressing macrophages are not a static population. Instead, they are a specialized subtype that emerges in response to specific physiological needs or pathological conditions.

Key Functions of GPNMB-Expressing Macrophages

When macrophages express GPNMB, their function is altered to help resolve inflammation. As a negative regulator of inflammatory responses, these macrophages reduce their production of pro-inflammatory cytokines, such as IL-6 and TNF-α. They also promote an increase in anti-inflammatory cytokines like IL-10, helping to quiet the immune response once a threat is neutralized.

The protein also enhances the cleanup capabilities of macrophages. Macrophages positive for GPNMB exhibit greater phagocytic activity, meaning they are more efficient at clearing away dead cells and other debris. This removal of dead cells, known as efferocytosis, is a component of resolving inflammation and initiating tissue repair.

GPNMB is also involved in cellular interactions that influence tissue remodeling. The protein can facilitate cell adhesion, helping macrophages bind to specific sites within tissues. It interacts with receptors like syndecan-4 on other cells, which can inhibit the activation of T cells. This interaction helps to dampen the adaptive immune response, preventing prolonged inflammation that could lead to tissue damage.

The Involvement of GPNMB Macrophages in Disease

The role of GPNMB-expressing macrophages is apparent in various diseases, where their function can be beneficial or detrimental. In cancer, these macrophages are often found within the tumor microenvironment. Their anti-inflammatory and T-cell suppressive functions can help the tumor evade the immune system. By binding to syndecan-4 on T cells, GPNMB suppresses their anti-cancer activity, contributing to tumor growth.

In neurodegenerative diseases like Parkinson’s and Alzheimer’s, the role of GPNMB-expressing macrophages is under investigation. The protein is found at increased levels in these conditions. Their enhanced ability to clear cellular debris could be protective by helping remove toxic protein aggregates. However, their modulation of inflammation in the brain is a delicate balance, and their precise contribution is still being determined.

GPNMB-positive macrophages are also implicated in metabolic disorders. In non-alcoholic steatohepatitis (NASH), a form of fatty liver disease, these macrophages infiltrate the liver and are associated with resolving injury. They help balance fibrosis (scarring) and fibrolysis (the breakdown of scar tissue). In lysosomal storage disorders like Gaucher disease, GPNMB levels are also elevated.

GPNMB Macrophages in Tissue Repair and Regeneration

GPNMB-expressing macrophages are involved in tissue repair and regeneration. Following an injury, an initial inflammatory phase clears pathogens and debris. These macrophages are important for transitioning from this inflammatory state to a healing phase, using their anti-inflammatory signaling to prevent the response from becoming chronic.

In the context of wound healing, GPNMB-positive macrophages contribute to several restorative processes. Their heightened phagocytic capacity allows them to efficiently clear away dead cells and remnants of the damaged extracellular matrix. This cleanup operation is a prerequisite for new tissue to be built, preparing the ground for regeneration.

These macrophages also actively support the rebuilding of tissue. They release factors that promote the growth of new cells and the formation of new blood vessels, a process called angiogenesis. This process supplies the healing tissue with oxygen and nutrients, making them an integral part of the body’s natural repair process.

Therapeutic Implications and Future Research of GPNMB Macrophages

The roles of GPNMB-expressing macrophages in disease and repair have opened possibilities for new medical treatments. One application is the use of GPNMB as a biomarker. Measuring levels of soluble GPNMB in the blood or detecting GPNMB-positive cells in tissue biopsies could help diagnose certain diseases, determine their severity, or monitor treatment effectiveness.

Targeting these macrophages directly is another therapeutic strategy. In diseases where they are detrimental, like certain cancers, treatments could block GPNMB’s function. For example, antibodies that bind to GPNMB could prevent it from suppressing T cells, allowing the immune system to attack the tumor. Conversely, where these macrophages are beneficial, therapies could aim to boost their numbers or function.

The soluble form of GPNMB itself might also have therapeutic potential. Administering this protein fragment could be used to dampen excessive inflammation or promote tissue healing in a controlled way. Researchers are still working to fully understand the complex signaling pathways GPNMB influences and how its function varies between different tissues and diseases.