Specialized immune cells called macrophages act as housekeepers, clearing cellular debris and responding to damage or infection. On the surface of some macrophages is a receptor known as TREM2 (triggering receptor expressed on myeloid cells 2). This receptor functions as a sensor that directs the macrophage’s activity, making it a subject of interest for its influence on various diseases.
The Role of TREM2 in Macrophage Function
The TREM2 receptor is fundamental to maintaining tissue health by acting as a sensor. It recognizes molecular patterns on dying cells or certain lipids, initiating a process called phagocytosis. This process involves the macrophage engulfing and digesting cellular debris, pathogens, or abnormal proteins.
Upon binding to a target, TREM2 initiates a signal cascade inside the macrophage by partnering with adaptor proteins. This internal signaling drives the physical act of engulfment and influences the macrophage’s behavior. The signals help reshape the cell’s cytoskeleton, which is necessary for the macrophage to move and surround its target.
Beyond cleanup duties, TREM2 signaling also modulates the inflammatory response. It helps suppress excessive inflammation, guiding the macrophage toward a state that promotes healing. This function prevents collateral damage to healthy tissues that can occur during a prolonged immune response.
The signals from the TREM2 receptor also support the macrophage’s health and longevity. The downstream pathways it activates are connected to cellular metabolism and survival. This ensures the macrophage has the energy and resources to perform its functions over extended periods, especially in environments with high cellular stress.
Involvement in Neurodegenerative Diseases
In the central nervous system, macrophages are known as microglia, where the TREM2 receptor is involved in neurodegenerative diseases like Alzheimer’s. Genetic studies have revealed that certain rare variants in the TREM2 gene can increase an individual’s risk for developing late-onset Alzheimer’s. This link has focused research on how microglial TREM2 function, or dysfunction, contributes to the disease.
Alzheimer’s disease involves the accumulation of amyloid-beta plaques and tau protein tangles. Healthy microglia manage this by clustering around amyloid plaques to clear them. TREM2 is involved in this process, signaling microglia to migrate toward and engulf the toxic protein aggregates. This action helps compact the plaques, potentially reducing their toxicity to surrounding neurons.
When TREM2 function is impaired by genetic mutations, this protective mechanism falters. Microglia with dysfunctional TREM2 are less efficient at migrating to and clustering around amyloid plaques. This failure can lead to more diffuse and potentially more harmful forms of amyloid spreading throughout the brain.
The influence of TREM2 extends to tau tangles, the other hallmark of Alzheimer’s. Evidence suggests that TREM2-mediated microglial activity can help limit the spread of toxic tau pathology. In the absence of functional TREM2, tau pathology may be exacerbated. TREM2 is also being investigated in other conditions like Parkinson’s disease and ALS, where clearing protein aggregates and managing neuroinflammation are also factors.
Connection to Cancer and Metabolism
TREM2-expressing macrophages are also active in cancer. Within the tumor microenvironment, tumor-associated macrophages (TAMs) often express high levels of TREM2. In this context, the receptor’s function appears to be co-opted by the tumor, contrasting with its protective role in the brain.
In cancers like hepatocellular carcinoma and certain sarcomas, TREM2 expression on TAMs is associated with a pro-tumorigenic phenotype. These TREM2-positive TAMs can suppress the activity of other immune cells, such as CD8+ T cells, that are responsible for killing cancer cells. They can also promote the formation of new blood vessels that supply the tumor with nutrients, fueling its growth.
The receptor’s role in lipid sensing also links it to metabolic disorders. In obesity, macrophages in adipose (fat) tissue express TREM2 to help manage lipid accumulation and inflammation. In atherosclerosis, the buildup of fatty plaques in arteries, macrophages also use TREM2. Within these plaques, macrophages become “foamy” by taking up large amounts of lipids, and TREM2 regulates this uptake and promotes their survival, influencing plaque progression.
Therapeutic Strategies Targeting TREM2
The dual nature of TREM2’s function has led to distinct therapeutic strategies. For neurodegenerative diseases like Alzheimer’s, the primary goal is to enhance the receptor’s activity. Researchers are developing agonistic antibodies, which are molecules designed to bind to and activate TREM2. The goal is to boost TREM2 signaling, making microglia more effective at clearing pathology and slowing disease progression.
These TREM2-activating antibodies have shown promise in preclinical models, demonstrating an ability to improve microglial migration toward plaques and enhance their phagocytic capabilities. Several of these agonist antibodies are now being tested in clinical trials for early-stage Alzheimer’s disease to see if these benefits translate to humans. One of the challenges for this approach is ensuring that enough of the antibody can cross the blood-brain barrier to reach the microglia in the brain.
In contrast, for certain cancers, the therapeutic strategy is to inhibit TREM2 function using antagonists. These inhibitory antibodies or molecules aim to prevent TREM2 from signaling. This can “reawaken” the anti-tumor immune response and make tumors more susceptible to other treatments, like checkpoint inhibitors.
This targeted approach of either activating or inhibiting the receptor depends on the disease context. The ability to modulate TREM2 activity offers a promising avenue for new treatments for conditions ranging from neurodegeneration to oncology. This field of research is highly active, with ongoing studies aiming to refine these strategies and identify which patients are most likely to benefit.