[PDF][PDF] Apoptotic cells induce a phosphatidylserine-dependent homeostatic response from phagocytes

RS Kiss, MR Elliott, Z Ma, YL Marcel, KS Ravichandran - Current Biology, 2006 - cell.com
RS Kiss, MR Elliott, Z Ma, YL Marcel, KS Ravichandran
Current Biology, 2006cell.com
Engulfment of apoptotic cells by phagocytes is important throughout development and adult
life [1, 2]. When phagocytes engulf apoptotic cells, they increase their cellular contents
including cholesterol and phospholipids, but how the phagocytes respond to this increased
load is poorly understood. Here, we identify one type of a phagocyte response, wherein the
recognition of apoptotic cells triggers enhanced cholesterol efflux (to apolipoprotein AI) from
macrophages. Phosphatidylserine (PS) exposed on apoptotic cells was necessary and …
Summary
Engulfment of apoptotic cells by phagocytes is important throughout development and adult life [1, 2]. When phagocytes engulf apoptotic cells, they increase their cellular contents including cholesterol and phospholipids, but how the phagocytes respond to this increased load is poorly understood. Here, we identify one type of a phagocyte response, wherein the recognition of apoptotic cells triggers enhanced cholesterol efflux (to apolipoprotein A-I) from macrophages. Phosphatidylserine (PS) exposed on apoptotic cells was necessary and sufficient to stimulate the efflux response. A major mechanism for this enhanced efflux by macrophages was the upregulation of the mRNA and protein for ABCA1, a membrane transporter independently linked to cholesterol efflux as well as engulfment of apoptotic cells [3, 4]. This increase in phagocyte ABCA1 levels required the function of nuclear receptor LXRα/β, a known regulator of cholesterol homeostasis in humans and mice [5]. Taken together, these data reveal a "homeostatic program" initiated in phagocytes that include a proximal membrane signaling event initiated by PS recognition, a downstream signaling event acting through nuclear receptors, and an effector arm involving upregulation of ABCA1, in turn promoting reverse cholesterol transport from the phagocytes. These data also have implications for macrophage handling of contents derived from apoptotic versus necrotic cells in atherosclerotic lesions [6].
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