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Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low‐density lipoprotein (LDL) and oxidized LDL immune complexes: role in phagocytosis and cytokine release

Oxidized low‐density lipoprotein (oxLDL) and oxLDL‐containing immune complexes (oxLDL‐IC) contribute to the formation of lipid‐laden macrophages (foam cells). Fcγ receptors mediate uptake of oxLDL‐IC, whereas scavenger receptors internalize oxLDL. We have previously reported that oxLDL‐IC, but not free oxLDL, activate macrophages and prolong their survival. Sphingomyelin is a major constituent of cell membranes and lipoprotein particles and acid sphingomyelinase (ASMase) hydrolyses sphingomyelin to generate the bioactive lipid ceramide. ASMase exists in two forms: lysosomal (L‐ASMase) and secretory (S‐ASMase). In this study we examined whether oxLDL and oxLDL‐IC regulate ASMase differently, and whether ASMase mediates monocyte/macrophage activation and cytokine release. The oxLDL‐IC, but not oxLDL, induced early and consistent release of catalytically active S‐ASMase. The oxLDL‐IC also consistently stimulated L‐ASMase activity, whereas oxLDL induced a rapid transient increase in L‐ASMase activity before it steadily declined below baseline. Prolonged exposure to oxLDL increased L‐ASMase activity; however, activity remained significantly lower than that induced by oxLDL‐IC. Further studies were aimed at defining the function of the activated ASMase. In response to oxLDL‐IC, heat‐shock protein 70B’ (HSP70B’) was up‐regulated and localized with redistributed ASMase in the endosomal compartment outside the lysosome. Treatment with oxLDL‐IC induced the formation and release of HSP70‐containing and IL‐1β‐containing exosomes via an ASMase‐dependent mechanism. Taken together, the results suggest that oxLDL and oxLDL‐IC differentially regulate ASMase activity, and the pro‐inflammatory responses to oxLDL‐IC are mediated by prolonged activation of ASMase. These findings may contribute to increased understanding of mechanisms mediating macrophage involvement in atherosclerosis.