Mechanisms of efferocytosis and its role in atherosclerosis

Phagocytosis of apoptotic cells (efferocytosis), is a crucial process in the human body for maintaining tissue homeostasis and immune defense. Defective efferocytosis can contribute to major forms of diseases such as auto-immune disorders, and possibly atherosclerosis and its complications. Obesity and Type 2 diabetes are highly correlated with atherosclerosis but the underlying mechanisms are poorly understood. Defective efferocytosis by macrophages is thought to increase necrotic core formation and inflammation in atherosclerotic lesions. This thesis investigates two different aspects concerning the molecular mechanisms of efferocytosis and its role in atherosclerosis in obese mice.;In Chapter II, I show that peritoneal macrophages from ob/ob mice have impaired efferocytosis, reflecting decreased association of the regulatory subunit of PI3K with phosphotyrosine signaling proteins and defective PI3K/AKT activation during uptake of apoptotic cells. The defect in efferocytosis is attributable at least in part to exposure of macrophages to increased concentrations of saturated free fatty acids (FFAs). A similar defect was induced by treating WT macrophages with saturated FFA/BSA complexes. Defects in efferocytosis and PI3K activation in ob/ob macrophages were reversed by treatment with IL-4 and activators of Peroxisome Proliferator-Activated Receptor (PPAR) gamma/delta, or long chain n-3 fatty acids. I also demonstrated defective macrophage efferocytosis in atherosclerotic lesions of high fat diet-fed ob/ob;Ldlr-/- mice, with the defect reversed by a fish oil diet rich in n-3 fatty acids. These findings suggest that in obesity and Type 2 diabetes elevated levels of saturated free fatty acids cause decreased macrophage efferocytosis, reflecting defective PPAR gamma/delta and PI3K activation, with adverse consequences for atherogenesis.;Efferocytosis is also known as an evolutionarily conserved process. The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans (C. elegans) gene that mediates efferocytosis. Data in Chapter III suggest that ABCA7 but not -A1 is a mammalian orthologue of CED-7 and ABCA7 regulates ERK signaling via LRP1 to mediate phagocytosis of apoptotic cells.;Together, these studies can provide new insights into the complicated process of efferocytosis in mammals and its role in atherosclerosis.