The Role of MFG-E8 in Glial-Neuronal Interactions and Neuroinflammation.

The interaction between neurons and glia in the brain is fundamental in keeping the brain healthy. Not only do glia help maintain homeostasis and structural integrity in the brain, they are critical in the removal of harmful material and dying cells. Microglia, which are similar to immune cells in the periphery of the body, are key phagocytic cells in the brain. In the peripheral immune system, macrophages secrete Milk Fat Globule Factor-E8 (MFG-E8) that recognizes phosphatidylserine "eat me" signals expressed on the surface of apoptotic cells. MFG-E8 then acts as a tether to attach the apoptotic cell to the macrophage and trigger a signaling cascade that stimulates the phagocytic capabilities of the macrophage, allowing the macrophage to engulf the dying cell. Meanwhile, an environment of anti-inflammation is created to protect the surrounding tissue. When this process becomes disrupted, inflammation and autoimmunity can result. MFG-E8 resides in the brain as well as in the periphery, and recently microglia were shown to express this protein. We propose that MFG-E8 acts in the brain via microglia as it does in the periphery via macrophages. Our hypothesis is that MFG-E8 plays a role in microglial phagocytosis of apoptotic neurons, and dysregulation of this process leads to neuroinflammation. Modulation of this mechanism is a potential target for drug discovery in neuroinflammatory disorders such as Alzheimer's disease. We have confirmed that microglia do produce MFG-E8 and the major signaling molecules necessary for phagocytic signaling. Our current focus is on demonstrating the involvement of MFG-E8 in phagocytosis of apoptotic neurons and determining if a similar pathway to the periphery is used in signaling this function. [ABSTRACT FROM AUTHOR]