The immune system contains specialized cells called macrophages, which function as the body’s “cleanup crew” by removing cellular debris and dead cells. To perform this function, macrophages have receptors on their surfaces that detect and respond to their environment. One of these is a protein receptor known as Mer Tyrosine Kinase, or MerTK.
The Function of the MerTK Receptor
Cell surface receptors act like locks that require a specific key to activate. For MerTK, the “keys” are molecules that appear on the surface of cells undergoing programmed cell death, or apoptosis. As a cell dies, it displays “eat-me” signals, which are recognized by bridging molecules like Gas6 and Protein S. These molecules then bind to and activate the MerTK receptor on a nearby macrophage.
This binding triggers a signaling cascade within the macrophage, initiating a process called efferocytosis. Efferocytosis is the mechanism by which the macrophage extends its membrane to envelop, or engulf, the dying cell. The cell is then broken down and its components are recycled. This clearance resembles a Pac-Man-like action, systematically removing apoptotic cells.
This process is not just about waste removal; it also sends a “calm down” signal. MerTK activation suppresses the production of pro-inflammatory substances inside the macrophage, ensuring the cleanup process does not trigger an immune alarm. By consuming the dead cell, the macrophage helps maintain a peaceful state in the surrounding tissue.
The Importance of Clearing Dead Cells
The efficient removal of dying cells through efferocytosis is necessary for maintaining tissue health. Billions of cells die daily as part of their normal life cycle. If these apoptotic cells are not cleared, they can disintegrate and spill their internal contents, which triggers an inflammatory response that, if it becomes chronic, can damage healthy tissues.
A failure to clear dead cells can also lead to autoimmune disorders. As cellular debris accumulates, the immune system may misidentify the body’s own proteins as foreign invaders. This confusion can lead to the production of antibodies against self-antigens, causing the immune system to attack healthy tissues and organs.
Disease Links to MerTK Malfunction
When the MerTK signaling system malfunctions, the consequences can be serious. The inability of macrophages to properly clear away dead cells contributes to a range of chronic inflammatory and autoimmune diseases.
Systemic Lupus Erythematosus (Lupus) is an autoimmune disease linked to MerTK malfunction. In individuals with lupus, a defect in efferocytosis leads to a buildup of apoptotic cell remnants. This cellular waste provides a source of self-antigens that stimulate the immune system to produce autoantibodies, leading to inflammation and damage to organs like the kidneys, skin, and joints.
Atherosclerosis, the hardening of the arteries, is also linked to faulty MerTK function. In artery walls, macrophages clear dead cells and excess lipids. When MerTK-mediated efferocytosis is impaired, dead foam cells and other debris accumulate, forming an inflammatory plaque. This plaque narrows the arteries and can lead to heart attacks or strokes.
MerTK dysfunction plays a part in retinal degeneration, such as Retinitis Pigmentosa. In this condition, light-sensing photoreceptor cells in the retina die. The resident macrophages, known as microglia, rely on MerTK to clear these dying cells. Inefficient clearance accelerates the degenerative process and contributes to vision loss as inflammation damages healthy photoreceptors.
The Role of MerTK in Cancer
Cancer cells can manipulate the MerTK pathway to their advantage. Tumors exploit MerTK’s anti-inflammatory “calm down” signal to protect themselves from the body’s immune defenses. This exploitation creates an immune-suppressive tumor microenvironment.
Within a tumor, rapid growth and a lack of nutrients cause a high rate of cell death, providing a constant supply of apoptotic cells. Macrophages in the tumor, called tumor-associated macrophages (TAMs), use MerTK to clear this debris. The continuous MerTK signaling keeps these TAMs in an anti-inflammatory and pro-repair state.
This anti-inflammatory state helps the cancer thrive. The TAMs release signals that suppress other immune cells, particularly T-cells that are responsible for killing cancer cells. The MerTK pathway thereby helps the tumor create a shield from the immune system, allowing it to grow and spread without being attacked.
Therapeutic Approaches Targeting MerTK
Given its dual role, the MerTK pathway is a target for therapeutic intervention. Scientists are developing strategies that either block or enhance MerTK activity, depending on the disease. The goal is to correct signaling imbalances that cause either excessive inflammation or immune suppression.
For cancer treatment, the primary strategy is MerTK inhibition. The goal is to develop drugs that block the MerTK receptor on tumor-associated macrophages. By turning off the anti-inflammatory signal, researchers hope to “reawaken” the immune system within the tumor microenvironment. These inhibitors are being explored as standalone treatments and in combination with other immunotherapies to enhance their effectiveness.
Conversely, for autoimmune and chronic inflammatory diseases, the goal is to activate or boost MerTK’s function. Enhancing the clearance of dead cells could reduce the chronic inflammation that drives conditions like lupus or atherosclerosis. Therapeutic strategies might involve developing molecules that mimic MerTK’s natural ligands or otherwise promote its signaling pathway, helping to restore the efficient cleanup of cellular debris.