Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis

被引：371

作者：

Sergin, Ismail ^{[1
]}

Evans, Trent D. ^{[1
]}

Zhang, Xiangyu ^{[1
]}

Bhattacharya, Somashubhra ^{[1
]}

Stokes, Carl J. ^{[1
]}

Song, Eric ^{[1
]}

Ali, Sahl ^{[1
]}

Dehestani, Babak ^{[1
]}

Holloway, Karyn B. ^{[1
]}

Micevych, Paul S. ^{[1
]}

Javaheri, Ali ^{[1
]}

Crowley, Jan R. ^{[2
]}

Ballabio, Andrea ^{[3
]}

Schilling, Joel D. ^{[1
,4
]}

Epelman, Slava ^{[5
]}

Weihl, Conrad C. ^{[6
]}

Diwan, Abhinav ^{[1
]}

Fan, Daping ^{[7
]}

Zayed, Mohamed A. ^{[8
]}

Razani, Babak ^{[1
,4
]}

机构：

[1] Washington Univ, Sch Med, Cardiovasc Div, Dept Med, Campus Box 8086,660 S Euclid Ave, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, Dept Med, 660S Euclid Ave, St Louis, MO 63110 USA

[3] Telethon Inst Genet & Med, Via Campi Flegrei 34, I-80078 Naples, Italy

[4] Washington Univ, Sch Med, Dept Pathol & Immunol, Campus Box 8086,660S Euclid Ave, St Louis, MO 63110 USA

[5] Univ Hlth Network, Peter Munk Cardiac Ctr, Toronto, ON M5G 2C4, Canada

[6] Washington Univ, Sch Med, Dept Neurol, Campus Box 8111,660S Euclid Ave, St Louis, MO 63110 USA

[7] Univ South Carolina, Dept Cell Biol & Anat, Sch Med, Columbia, SC 29209 USA

[8] Washington Univ, Sch Med, Dept Surg, 660S Euclid Ave, St Louis, MO 63110 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

TREHALOSE; MICE; CELLS; CHOLESTEROL; DISEASE; TFEB; CLEARANCE; INFLAMMASOMES; PROGRESSION; ASSOCIATION;

D O I：

10.1038/ncomms15750

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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-1 beta 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.

引用

页数：20

共 49 条

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