PTEN Negatively Regulates Engulfment of Apoptotic Cells by Modulating Activation of Rae GTPase

Efficient clearance of apoptotie cells by phagocytes (efferocytosis) is critical for normal tissue homeostasis and regulation of the immune system. Apoptotic cells are recognized by a vast repertoire of receptors on macrophage that lead to transient formation of phosphatidylinosito1-3,4,5-trisphosphate [PtdIns(3,4,5)P3] and subsequent cytoskeletal reorganization necessary for engulfment. Certain P13K isoforms are required for engulfment of apoptotic cells, but relatively little is known about the role of lipid phosphatases in this process. In this study, we report that the activity of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatidylinositol 3-phosphatase, is elevated upon efferocytosis. Depletion of PTEN in macrophage results in elevated PtdIns(3,4,5)P3 production and enhanced phagocytic ability both in vivo and in vitro, whereas overexpression of wild-type.PTEN abrogates this process. Loss of PTEN in macrophage leads to activation of the pleckstrin homology domain-containing guanine-nucleotide exchange factor Vav1 and subsequent activation of Racl GTPase, resulting in increased amounts of F-actin upon engulfment of apoptotic cells. PTEN disruption also leads to increased production of anti-inflammatory cytokine IL-10 and decreased production of proinflammatory IL-6 and TNF-et upon engulfment of apoptotic cells. These data suggest that PTEN exerts control over efferocytosis potentially by regulating PtdIns(3,4,5)P3 levels that modulate Rac GTPase and F-actin reorganization through Vavl exchange factor and enhancing apoptotic cell-induced anti-inflammatory response. The Journal of Immunology, 2011, 187: 5783-5794.