New cells are constantly generated to replace old and unwanted cells dying by apoptosis, to maintain tissue integrity. Such turnover occurs in the human body at an astonishing rate of approximately 1 million cells per second! The cells that die are recognized and removed by cells called phagocytes, and this occurs silently and with remarkable efficiency. Defects in removal of apoptotic cells predispose to inflammation and autoimmunity, due to leakage of dying cell contents. Many tissues have more than one type of phagocyte, but little is known about how phagocytes communicate with each other and non-phagocytic cells within a tissue. In this proposal, I will use the liver as a model system to study crosstalk between phagocytes and their communication with non-engulfing cells and to elucidate the role of apoptotic cell clearance in clinically relevant models of liver disease. ELMO proteins are key components of the machinery that phagocytes use to engulf dying cells, and Elmo1 has been linked to liver disease in genome-wide association studies. By deleting Elmo1 and Elmo2 genes in Kupffer cells and monocytes and Elmo2 and Elmo3 in hepatocytes, I will mechanistically test this association in models of liver disease. Further I will boost apoptotic cell clearance via a novel chimeric phagocyte receptor to test whether this can ameliorate liver disease. These novel and impactful studies will have broad implications to basic biology and future therapies for liver diseases.