TFEB and trehalose drive the macrophage autophagy-lysosome system to protect against atherosclerosis

ABSTRACT

In the atherosclerotic plaque, macrophages are the key catabolic workhorse responsible for clearing lipid and dead cell debris. To survive the highly proinflammatory and lipotoxic plaque environment, macrophages must adopt strategies for maintaining tight homeostasis and self-renewal. Macroautophagy/autophagy is a pro-survival cellular pathway wherein damaged or excess cellular cargoes are encapsulated by a double-membrane compartment and delivered to the lysosome for hydrolysis. Previously, macrophage-specific autophagy deficiency has been shown to be atherogenic through several complementary mechanisms including hyperactivation of the inflammasome, defective efferocytosis, accumulation of cytotoxic protein aggregates, and impaired lipid degradation. Conversely, in a recent study we hypothesized that enhancing the macrophage autophagy-lysosomal system through genetic or pharmacological means could protect against atherosclerosis. We demonstrated that TFEB, a transcription factor master regulator of autophagy and lysosome biogenesis, coordinately enhances the function of this system to reduce atherosclerotic plaque burden. Further, we characterized the disaccharide trehalose as a novel inducer of TFEB with similar atheroprotective effects. Overall, these findings mechanistically interrogate the importance and therapeutic promise of a functional autophagy-lysosome degradation system in plaque macrophage biology.

KEYWORDS:

• Apoptosis
• atherosclerosis
• autophagy
• inflammation
• lysosome
• macrophage
• p62
• protein aggregation
• TFEB
• trehalose

Disclosure of potential conflict of interest

The authors have nothing relevant to disclose.

Additional information

Funding

American Diabetes Association [grant number 1-18-IBS-029]; National Heart, Lung, and Blood Institute [grant number F31 HL132434]; National Heart, Lung, and Blood Institute [grant number R01 HL125838]; National Institute of Diabetes and Digestive and Kidney Diseases [grant number P30 DK020579]; U.S. Department of Veterans Affairs [grant number I01 BX003415].