Acid sphingomyelinase in macrophage apoptosis

This article presents an overview of the recent progress in understanding metabolic and functional interrelationships of biologically active sphingolipids related to the sphingomyelin signal transduction pathway in relation to the regulation of apoptosis in macrophages.

Ceramide generation is an essential, early step in apoptosis in numerous systems. There are several mechanisms for ceramide generation, including activation of plasma membrane, lysosomal, nuclear, and mitochondrial sphingomyelinases, and induction of de-novo synthesis of ceramide. Some of the proapoptotic actions of ceramide are to facilitate assembly of death receptor complexes in the plasma membrane, to prevent the activation of protein kinase B/Akt, and to promote the activation of caspase 3. Failure of macrophages in developing atherosclerotic plaques to undergo apoptosis is a possible contributor to plaque expansion. At low concentrations, oxidized LDL has been shown to prevent apoptosis induced by growth factor withdrawal in cultured bone marrow-derived macrophages, in part by inhibiting sphingomyelinase and preventing generation of ceramide. At high concentrations, however, oxidized LDL can induce apoptosis or necrosis of macrophages.

Sphingolipid signal transduction pathways play an important role in the regulation of growth and survival pathways in macrophages. These are directly relevant to the pathogenesis of a variety of chronic inflammatory disorders, including atherosclerosis.