The inflammatory cytokine response of cholesterol-enriched macrophages is dampened by stimulated pinocytosis

Two features of advanced atherosclerotic lesions are large numbers of macrophages and a heightened state of inflammation. Some of the macrophages appear to be enriched with free cholesterol (FCMphis), and we have shown that this process induces the synthesis and secretion of inflammatory cytokines, including TNF-alpha and IL-6. However, lesions contain many other macrophages that are not FC-enriched (non-FCMphis). Therefore, we sought to understand how the interaction of these two populations of macrophages would influence the inflammatory response. We show here that non-FCMphis possess a robust ability to deplete TNF-alpha and IL-6 secreted by FCMphis. The mechanism involves enhanced pinocytic uptake and lysosomal degradation of the FCMphi-secreted cytokines by the non-FCMphis. The FCMphis contribute directly to this process by secreting pinocytosis-stimulatory factors that act on non-FCMphis but not on the FCMphis themselves. One of these pinocytosis-stimulatory factors is M-CSF, which is induced by a process involving cholesterol trafficking to the endoplasmic reticulum and signaling through PI-3K and ERK MAPK pathways. However, one or more other FCMphi-secreted factors are also required for stimulating pinocytosis in non-FCMphis. Thus, FCMphis secrete inflammatory cytokines as well as factors that promote the eventual pinocytosis and degradation of these cytokines by neighboring macrophages. This process may normally serve to prevent prolonged or disseminated effects of inflammatory cytokines during inflammation. Moreover, possible perturbation of stimulated pinocytosis during the progression of advanced atherosclerosis may contribute to the heightened inflammatory state of these lesions.