Abstract 372: CD36 Signaling Regulates Autophagy to Limit Macrophage Cholesterol Accumulation
Autophagy regulates cholesterol mobilization from lipid droplets, a rate-limiting step in macrophage reverse cholesterol transport. Here we investigated the molecular mechanisms of autophagy activation in macrophage foam cells and atherosclerotic plaque. Immunohistochemical staining of human atherosclerotic lesions for LC3 revealed elevated levels of this autophagy marker, particularly in macrophages located in the rupture-prone ‘shoulder region’ of the lesions. This suggests a ‘frustrated autophagy’ in these macrophages, which play important roles in the transition of plaques to a vulnerable state. Notably, we find that macrophages faced with prolonged lipid challenge in vitro exhibit a progressive defect in autophagic flux over time. Pharmacologic stimulation of autophagy in lipid-loaded macrophages enhances cholesterol efflux, suggesting that increasing arterial macrophage autophagy may be anti-atherogenic. However, the molecular mechanisms by which autophagy is stimulated in macrophage foam cells are unclear. Autophagy is rapidly activated in macrophages exposed to oxLDL. Given the role of scavenger receptors in the internalization and signaling response to oxLDL, we investigated whether autophagy activation in foam cells requires CD36. Using Cd36-/- macrophages, we find that oxLDL-induced autophagy is severely impaired compared to WT. Interestingly, preventing dynamin-dependent oxLDL uptake by CD36 does not alter oxLDL-induced autophagy, suggesting that CD36-signaling is sufficient to trigger autophagic activation. Previous studies have shown that CD36 mediates autonomous signaling via Src and MAP kinases, or pairs with Toll-like receptors, including TLR4, to induce the signaling response to oxLDL. Using macrophages from knockout mice, we show that oxLDL-triggered autophagy is intact in the absence of TLR4 or its adaptor MyD88. However, selective inhibition of Src kinases or the MAP kinases Erk and Jnk abolishes induction of LC3 in response to oxLDL. Accordingly, we observe a marked reduction in autophagy levels in plaque macrophages from Apoe-/-Cd36-/- mice on western diet. Together, our data indicate a role for CD36 signaling in limiting cholesterol accumulation in plaque macrophages via induction of autophagy.
- © 2013 by American Heart Association, Inc.