Abstract
Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy–lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy–lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy–lysosomal biogenesis and show trehalose’s ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease.
Highlights
Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque
Using the accumulation of the autophagy marker p62/SQSTM1, a chaperone for selective autophagy of cargo such as protein aggregates, we have previously demonstrated that macrophages develop a progressive autophagy dysfunction in the developing plaque[3,6]
By overexpressing TFEB in cultured macrophages, we recently showed the ability of autophagy–lysosomal biogenesis to reverse the autophagy–lysosomal dysfunction instigated by atherogenic lipids and to have several functional benefits such as induction of cholesterol efflux, dampening of inflammasome activation and clearance of polyubiquitinated protein aggregates[12]
Summary
Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. By overexpressing TFEB in cultured macrophages, we recently showed the ability of autophagy–lysosomal biogenesis to reverse the autophagy–lysosomal dysfunction instigated by atherogenic lipids and to have several functional benefits such as induction of cholesterol efflux, dampening of inflammasome activation and clearance of polyubiquitinated protein aggregates[12]. It remains unclear how autophagy–lysosome dysfunction manifests and progresses in atherosclerotic plaques, and whether enhancing macrophage autophagy–lysosomal biogenesis can be effective against atherosclerosis. Owing to trehalose’s ability to induce autophagy and ameliorate various protein aggregation neurodegenerative diseases and our finding of TFEB as an autophagy inducer of protein aggregates, we became interested in evaluating the effects of trehalose in the induction of macrophage TFEB, autophagy–lysosomal biogenesis and atherosclerosis
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