Project Summary Efficient detection and clearance of apoptotic cells is essential in the maintenance of immune tolerance and tissue homeostasis. Phagocytes are responsible for removal of dying cells; however, defects in recognition or engulfment of apoptotic cells can lead to chronic inflammation and autoimmune disease. Accumulation of apoptotic cells in tissues has been associated with the autoimmune disease systemic lupus erythematosus (SLE), and several receptors on phagocytes responsible for the clearance of apoptotic debris have been identified. We previously identified the scavenger receptor expressed on endothelial cells-1 (SCARF1) as the receptor for apoptotic cells on dendritic cells via interactions with C1q/phosphatidylserine complexes on the dead cells (Ramirez-Ortiz et.al.; Nature Immunology). Loss of SCARF1 results in impaired uptake of apoptotic cells in vitro and in vivo, with accumulation of cell corpses in tissues and blood. Consequently, SCARF1-deficient mice develop lupus-like autoimmune disease. Our previous findings revealed that SCARF1 is a non-redundant efferocytosis receptor; however, additional work is needed to identify the mechanisms necessary for SCARF1-mediated removal of apoptotic cells and prevention of spontaneous autoimmunity in vivo. We hypothesize that SCARF1 plays an essential role in the physiological clearance of apoptotic debris, and that dysregulated or loss of SCARF1 expression on phagocytes leads to impaired AC uptake, loss of immune self-tolerance and development of autoimmunity. We propose to define the domains in SCARF1 that mediate recognition, signaling and removal of apoptotic cells and determine the relative contribution of SCARF1 in radioresistant cells vs hematopoietic cells. A comprehensive understanding of all the processes required for effective apoptotic cell removal can identify new targets not only for Lupus, but for many autoimmune, metabolic and infectious diseases.

Project Narrative Our immune system maintains tissue homeostasis by rapidly and efficiently clearing infected or damaged cells. When this essential process fails, apoptotic debris accumulates, leading to the development of chronic inflammatory diseases like systemic lupus erythematosus. We propose to identify and characterize the mechanisms by which SCARF1 (a key protein involved in clearing dead cells) protects against autoimmunity, and successful completion of the proposed work will aid in the development of new targeted therapies for autoimmune diseases.