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Nat Commun. 2017 Jun 7;8:15750. doi: 10.1038/ncomms15750.

Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis.

Author information

1
Department of Medicine, Cardiovascular Division, Washington University School of Medicine, Campus Box 8086, 660 S Euclid Avenue, St Louis, Missouri 63110, USA.
2
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660S Euclid Avenue, St Louis, Missouri 63110, USA.
3
Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
4
Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8086, 660S. Euclid Avenue, St Louis, Missouri 63110, USA.
5
Peter Munk Cardiac Center, University Health Network, Toronto, Ontario, Canada M5G 2C4.
6
Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660S. Euclid Avenue, St Louis, Missouri 63110, USA.
7
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29209, USA.
8
Department of Surgery, Washington University School of Medicine, 660S. Euclid Avenue, St Louis, Missouri 63110, USA.

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.

PMID:
28589926
PMCID:
PMC5467270
DOI:
10.1038/ncomms15750
[Indexed for MEDLINE]
Free PMC Article

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