Phagocytosis of Apoptotic Cells by Macrophages Induces Novel Signaling Events Leading to Cytokine-Independent Survival and Inhibition of Proliferation: Activation of Akt and Inhibition of Extracellular Signal-Regulated Kinases 1 and 2

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Abstract
Recent evidence indicates that phagocytic clearance of apoptotic cells, initially thought to be a silent event, can modulate macrophage (Mφ) function. We show in this work that phagocytic uptake of apoptotic cells or bodies, in the absence of serum or soluble survival factors, inhibits apoptosis and maintains viability of primary cultures of murine peritoneal and bone marrow Mφ with a potency approaching that of serum-supplemented medium. Apoptotic uptake also profoundly inhibits the proliferation of bone marrow Mφ stimulated to proliferate by M-CSF. While inhibition of proliferation is an unusual property for survival factors, the combination of increased survival and decreased proliferation may aid the Mφ in its role as a scavenger during resolution of inflammation. The ability of apoptotic cells to promote survival and inhibit proliferation appears to be the result of simultaneous activation of Akt and inhibition of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and ERK2 (ERK1/2). While several activators of the innate immune system, or danger signals, also inhibit apoptosis and proliferation, danger signals and necrotic cells differ from apoptotic cells in that they activate, rather than inhibit, ERK1/2. These signaling differences may underlie the opposing tendencies of apoptotic cells and danger signals in promoting tolerance vs immunity.