Interleukin-34, or IL-34, is a protein that sends signals between cells, placing it in a category of molecules known as cytokines. These proteins are fundamental to how the body coordinates complex processes, especially within the immune system. Identified more recently than many other cytokines, its functions are still being uncovered, opening new avenues for understanding how the body manages the lifecycle of certain immune cells and its involvement in various diseases.
The Biological Role of IL-34
In a healthy state, IL-34’s primary function is to regulate the development, survival, and activity of immune cells called myeloid cells, which include macrophages. It accomplishes this by binding to the colony-stimulating factor 1 receptor (CSF-1R) on the surface of these cells. This interaction initiates a cascade of signals inside the cell, much like a key fitting into a lock.
This signaling is important for maintaining macrophages in specific tissues. For instance, IL-34 produced by skin cells called keratinocytes supports Langerhans cells, a type of macrophage that acts as an immune sentinel in the skin. Similarly, IL-34 secreted by neurons is necessary for the maintenance of microglia, the brain’s resident macrophage population.
While another protein called CSF-1 can also bind to the same receptor, IL-34 acts as a tissue-specific ligand. Its production in locations like the skin and brain provides localized control over these immune cells. This precise regulation highlights a sophisticated system for maintaining immune readiness in different parts of the body.
IL-34 in the Immune System and Inflammation
The balanced role of IL-34 can be disrupted in certain disease states, leading to chronic inflammation. In conditions such as rheumatoid arthritis and inflammatory bowel disease, the body produces excessive amounts of IL-34 in affected tissues. This overproduction fuels a harmful cycle by promoting the accumulation and activation of macrophages, which are major drivers of the inflammatory process.
In rheumatoid arthritis, for example, cells in the joint lining are stimulated to release high levels of IL-34. This floods the joint space with the cytokine, which causes macrophage precursors to mature and release other pro-inflammatory substances. The result is persistent inflammation that damages cartilage and bone, leading to the pain and joint destruction characteristic of the disease.
The Connection to Neurological Health
Within the central nervous system, IL-34 is necessary for the maintenance of microglia, the brain’s specialized immune cells. Neurons consistently produce IL-34 to support the survival and function of these cells, which monitor the brain’s environment, remove cellular debris, and protect against pathogens. This relationship preserves the brain’s immune homeostasis under normal conditions.
However, the IL-34/microglia connection can become a double-edged sword in neurological disease. The dysregulation of IL-34 levels is implicated in neuroinflammatory and neurodegenerative disorders. For example, IL-34 production can increase in response to neuronal injury, which may initially be a protective survival signal for damaged neurons.
This same mechanism can contribute to a harmful, chronic inflammatory state in diseases like Alzheimer’s or multiple sclerosis. In these conditions, the altered signaling can cause microglia to become overactive, releasing inflammatory molecules that damage neurons and worsen disease progression. Researchers are investigating how this IL-34/microglia axis contributes to this neurotoxic environment.
IL-34’s Impact on Cancer
The influence of IL-34 extends to oncology, where it can contribute to cancer progression by manipulating the tumor microenvironment. This environment is a complex ecosystem of cancer cells, blood vessels, and immune cells. Some cancer cells have developed the ability to produce their own IL-34.
By secreting IL-34, tumors can recruit and sustain a population of specialized immune cells known as tumor-associated macrophages (TAMs). Instead of attacking the cancer, these TAMs are reprogrammed to help it thrive. They contribute to the construction of new blood vessels that supply the tumor with oxygen and nutrients, a process called angiogenesis.
These TAMs can also suppress the activity of other immune cells, such as T-cells, that would normally identify and destroy cancer cells. This creates an immunosuppressive shield around the tumor, allowing it to grow unchecked. The presence of IL-34 and the resulting accumulation of TAMs have been linked to poorer prognoses in various types of cancer.
Therapeutic Research and Future Directions
Because of its role in driving inflammation and supporting tumor growth, IL-34 is a target for the development of new therapies. Scientists are focused on creating treatments that can interrupt the signaling between IL-34 and its receptor, CSF-1R. The leading strategy involves designing monoclonal antibodies engineered to find and neutralize IL-34.
These therapeutic antibodies would work by binding directly to the IL-34 cytokine, preventing it from attaching to the CSF-1R receptor on macrophages and other cells. In rheumatoid arthritis, blocking IL-34 could reduce the number of inflammatory macrophages in the joints, alleviating inflammation and preventing further damage.
In cancer, an IL-34-blocking antibody could cut off the support system for tumors by depleting the tumor-associated macrophages that help them grow and evade the immune system. This strategy represents a promising avenue of research aimed at developing more targeted and effective treatments for a range of challenging diseases.