| The Tyro3/Axl/Mertk(TAM) family of receptors is important for phagocytosis of apoptotic cells, cytokine regulation, and suppression of autoimmune disease. Mice lacking Mertk present with a Systemic Lupus Erythematosus-like syndrome; however, the etiology of the autoimmune phenotype in the mertk -/- mice is unknown. As such, our hypothesis is that Mertk is regulating innate immune responses that prevent the initiation of autoimmune disease. This dissertation examines the role of the TAM family of receptors in (1) the clearance and killing of bacteria, (2) the regulation of immune cells in the peritoneal cavity, and (3) the regulation of cytoplasmic dsDNA-induced cell death through the regulation of p202. Chapter 2 shows the TAM receptors are dispensable for phagocytosis and killing of bacteria. Chapter 3 shows, Mertk regulates the immigration and the number of immune cells in the peritoneal cavity, particularly the T cells and B cells. In addition, this increase in peritoneal cells correlates to autoantibody formation found only in mertk-/- mice and not axl -/- or tyro3-/-. Finally, Chapter 4 shows that Mertk suppresses expression of the lupus susceptibility factor, p202, and that p202 may rescue macrophages from cytoplasmic dsDNA-induced cell death. These studies have clarified the literature with regards to TAM receptor family and bacteria clearance, have provided new insights to the autoimmune phenotype associated with the under studied peritoneal cavity, and have established a novel mechanism by which Mertk regulates death of APCs which may be critical in preventing the development of autoimmune disease. |
