Abstract 163: Induction of Lysosomal Biogenesis in Macrophages Reduces Atherosclerosis in an Autophagy-dependent Manner

Abstract

Recent reports of the proatherogenic phenotype of mice with a macrophage-specific autophagy deficiency have renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of processing both exogenous material such as excess atherogenic lipids and endogenous cargo that includes dysfunctional proteins and organelles via autophagy. Previously we demonstrated that oxidized LDL and cholesterol crystals, two of the commonly encountered lipid species in the atherosclerotic plaque, create a profound lysosomal and autophagy dysfunction in cultured macrophages. Overexpression of TFEB, a transcription factor that is the only known master regulator of lysosomal and autophagy biogenesis, in macrophages initiates a robust prodegradative response including induction of lysosomal and autophagy genes. This in turn ameliorates several deleterious effects of the lipid-mediated dysfunction, namely the blunting of inflammasome activation, enhancing cholesterol efflux, and accelerating the degradation of protein aggregates. Our in vitro data suggest that the induction of a lysosomal biogenesis program in macrophages can have atheroprotective effects. Indeed, myeloid-specific TFEB overexpression in mice significantly reduces atherosclerotic plaque burden as well as plaque complexity as gauged by reduced necrotic core and markers of apoptosis. Interestingly, this protection is autophagy-dependent since these TFEB-overexpressing mice on a background of myeloid-specific autophagy (ATG5)-deficiency no longer demonstrate plaque reduction. Mechanistically, this indicates that suppression of the inflammasome and enhancement of cholesterol efflux and protein aggregate removal is dependent on the TFEB-autophagy axis. Taken together, our data support the notion that harnessing the prodegradative response in macrophages via TFEB can be atheroprotective and provides the impetus to evaluate mechanisms by which macrophage lysosomal and autophagy biogenesis can be modulated therapeutically.