Abstract 4: Enhancing the Ability of Macrophages to Orchestrate Selective Autophagy and Lysosomal Biogenesis Protects Against Atherosclerosis

Abstract

The autophagy-lysosome system is a catabolic cellular mechanism that degrades dysfunctional proteins and organelles. The pro-atherogenic phenotype of mice with macrophage-specific autophagy deficiency (ATG5-/-) confirm the importance of this degradation system in the pathogenesis of atherosclerosis. The mechanistic basis appears to involve a two-step process in macrophages: the development of lysosomal dysfunction/membrane integrity by atherogenic lipids followed by an inability of lysosomes to handle and degrade cargo supplied by autophagy. A prominent sequelae of such blockage is the accumulation of cytoplasmic inclusions composed of polyubiquitinated protein aggregates and organelles which are normally targeted for selective autophagy by the protein chaperone p62. In order to stimulate the degradative capacity of macrophages, we developed mice with macrophage-specific overexpression of TFEB, a master transcriptional activator of both autophagy and lysosomal biogenesis. Macrophage TFEB ameliorated several deleterious effects of atherogenic lipids, namely the blunting of inflammasome activation, enhancing cholesterol efflux, accelerating the degradation of protein aggregates, and decreasing apoptosis. In vivo, macrophage TFEB overexpression reduced both plaque burden and plaque complexity in pro-atherogenic ApoE-/- mice fed a Western diet. Interestingly, TFEB’s atheroprotective effects were not only abrogated in the background of macrophage autophagy deficiency (ATG5-/-) but also in the background of p62-deficiency (p62-/-) suggesting the critical importance of selective autophagy and degradation of p62-enriched protein aggregates. Taken together, these data support the induction of a holistic pro-degradative response in macrophages (i.e. selective autophagy followed by lysosomal degradation) as a viable therapeutic strategy in atherosclerosis.