Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis

Ismail Sergin, Trent D. Evans, Xiangyu Zhang, Somashubhra Bhattacharya, Carl J. Stokes, Eric Song, Sahl Ali, Babak Dehestani, Karyn B. Holloway, Paul S. Micevych, Ali Javaheri, Jan R. Crowley, Andrea Ballabio, Joel D. Schilling, Slava Epelman, Conrad C. Weihl, Abhinav Diwan, Daping Fan, Mohamed A. Zayed and Babak Razani ()
Additional contact information
Ismail Sergin: Washington University School of Medicine
Trent D. Evans: Washington University School of Medicine
Xiangyu Zhang: Washington University School of Medicine
Somashubhra Bhattacharya: Washington University School of Medicine
Carl J. Stokes: Washington University School of Medicine
Eric Song: Washington University School of Medicine
Sahl Ali: Washington University School of Medicine
Babak Dehestani: Washington University School of Medicine
Karyn B. Holloway: Washington University School of Medicine
Paul S. Micevych: Washington University School of Medicine
Ali Javaheri: Washington University School of Medicine
Jan R. Crowley: Metabolism, and Lipid Research, Washington University School of Medicine
Andrea Ballabio: Telethon Institute of Genetics and Medicine
Joel D. Schilling: Washington University School of Medicine
Slava Epelman: Peter Munk Cardiac Center, University Health Network
Conrad C. Weihl: Washington University School of Medicine
Abhinav Diwan: Washington University School of Medicine
Daping Fan: University of South Carolina School of Medicine
Mohamed A. Zayed: Washington University School of Medicine
Babak Razani: Washington University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-20

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15750

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