The Role of Ceramide in the Clearence of Apoptotic Cells

Abstract

Cell fusion is a critical physiological process involving the specific interaction of lipid molecules that reside on the plasma membrane of all cells. The clearance of apoptotic cells (efferocytosis) requires the recognition and subsequent fusion of alveolar macrophages with those membranes of apoptotic cells that display a phosphatidylserine (PS) on the outer membrane, allowing for the physiological clearance of dead and/or dying cells. Recognition of this PS group by macrophages has critical importance as inefficient clearance of apoptotic cells may lead to localized inflammation that may exacerbate the pathogenesis of disease, such as that observed in emphysema. However, the biochemical mechanisms underlying cell fusion and efferocytosis remain unclear. Because ceramide-induced changes in biological membrane composition may have profound effects on cellular functions, we studied the biological effect of ceramide on plasma membrane fusion using model membranes. To do this we examined the inter- and intra-membrane forces of model membranes containing different ratios of PS:PC (phosphatidylcholine) in the presence of ceramides using SAXS and solid-state deuterium NMR. The addition of ceramides to the model membranes reduced the equilibrium spacing between membranes and increased the order of lipid chains. In a complementary cell culture model of engulfment using alveolar macrophages and model membranes, the incubation of either macrophages or model membranes with ceramides reduced the engulfment efficiency significantly. These data demonstrate that ceramide plays a critical role in the processes that lead to the recognition of PS and the subsequent fusion between plasma membranes. These studies suggest that modulating ceramide levels may lead to more efficient efferocytosis and thereby may attenuate lung tissue inflammation in emphysematous lungs.