The purpose of this proposal is to determine the biological relevance of Mer in the clearance of apoptotic cells by macrophages and to delineate in a mechanism that would account for the recognition, phagocytosis and anti-inflammatory consequence of clearing apoptotic cells by macrophages. A mechanism for recognition and update of apoptotic cells and the signal transduction pathway(s) triggered by apoptotic cells is still poorly understood. The hypothesis is Mer/Tyro3/Axl Receptor Tyrosine Kinases facilitate phagocytosis of apoptotic cells. Our preliminary (in vivo and in vitro) studies strongly suggest that Mer, a receptor tyrosine kinase expressed on macrophages, is involved in mediating the clearance of apoptotic cells and appears to modulate an anti-inflammatory response. Mice with a mutated Mer cytoplasmic signaling kinase domain (merkd) have macrophages that are defective in suppressing pro-inflammatory cytokines such as TNF-? and are defective in phagocytizing apoptotic cells. Furthermore, we presume that this defect is clinically relevant in that merkd mice produce elevated serum IgM autoantibodies and kidney shows pathology. Indeed, evidence is accruing that apoptotic cells can contribute to pathogenesis of autoimmune diseases, and that a high burden of apoptotic cells may provide an important route to autoantibody production as it has been implicated in SLE. Investigating the process involved in recognition and clearance of apoptotic cells may provide insights towards controlling inflammation and autoimmune disorders. Towards this goal, we propose to investigate the process involved in the clearance of apoptotic cells both in vivo and in vitro through novel receptor tyrosine kinases, Axl, Mer, and Tyro3 expressed on macrophages.
