The PROS1/TAM phagocytosis mechanism deals with different cell death modalities
2The Hebrew University, Institute for Drug Research, Department of Pharmacology, Israel
Tyro3, Axl, and MerTK (TAM), which constitute the TAM family of tyrosine kinase receptors mediate the phagocytosis of dying cells, as well as the “pruning” of fragments of living cells. This occurs in numerous cell types and is important for maintaining healthy tissues and to allow tissue repair in diseased conditions. While more is known about phagocytosis of dying cells by peripheral immune cells, much remains to be understood about phagocytosis in the central nervous system (CNS), mainly performed by microglia - the CNS immune cells.
To investigate TAM function in microglial phagocytosis, we generated mice lacking the TAM agonist Protein S (PROS1) in microglia. We use Pros1-deficient mice (Pros1-cKO) to understand how this pathway facilitates phagocytosis of different moieties: apoptotic cells, live cell portions, necrotic cells following injury, and even degraded myelin particles.
Primary Pros1-cKO microglia showed a decreased phagocytic capacity of myelin fragments, which was rescued by adding exogenous PROS1. In-vivo, Pros1-cKO brains had delayed clearance of dying neurons undergoing programmed cell death. Interestingly, the same molecules mediate the phagocytosis of necrotic cells following injury, as well as the uptake of degraded myelin in-vivo.
Taken together, our work provides a broad understanding of the robust repertoire of PROS1 mediated phagocytosis which facilitates the clearance of live cell fractions, as well as cells undergoing different cell death modalities, including programmed cell death and traumatized cells. The impact on inflammation, tissue repair and the therapeutic potential of this pathway will be discussed.