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Protective Role of Autophagy in Nlrp3 Inflammasome Activation and Medial Thickening of Mouse Coronary Arteries.


ABSTRACT: We hypothesized that autophagy and associated lysosome function serve as a critical modulator during Nod-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome activation on proatherogenic stimuli. We first demonstrated that 7-ketocholesterol stimulated Nlrp3 inflammasome formation and activation as shown by increased colocalization of inflammasome components [Nlrp3 versus apoptosis associated speck-like protein (Asc) or caspase-1] and enhanced cleavage of caspase-1 into active caspase-1 to generate IL-1? in coronary artery smooth muscle cells. Deletion of the CD38 gene (CD38-/-) that regulates lysosome function and autophagic flux also led to Nlrp3 inflammasome formation and activation. In the presence of rapamycin, the effects of either 7-ketocholesterol treatment or CD38 gene deletion were abolished. The autophagy inhibitor spautin-1 and the lysosome function blocker bafilomycin A1 also enhanced Nlrp3 inflammasome formation and activation. In animal experiments, we found that increased colocalization of Nlrp3 versus Asc or caspase-1 enhanced IL-1? accumulation and caspase-1 activity in the coronary arterial wall of CD38-/- mice on the Western diet compared with CD38+/+ mice. This increased colocalization was blocked by treatment with rapamycin but enhanced by chloroquine, a water-soluble blocker of autophagic flux. Morphologic examinations confirmed that the media of coronary arteries was significantly thicker in CD38-/- mice on the Western diet than CD38+/+ mice. In conclusion, the deficiency of autophagic flux promotes Nlrp3 inflammasome formation and activation in coronary artery smooth muscle cells on proatherogenic stimulation, leading to medial thickening of the coronary arterial wall.

SUBMITTER: Yuan X 

PROVIDER: S-EPMC6334256 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Protective Role of Autophagy in Nlrp3 Inflammasome Activation and Medial Thickening of Mouse Coronary Arteries.

Yuan Xinxu X   Bhat Owais M OM   Meng Nan N   Lohner Hannah H   Li Pin-Lan PL  

The American journal of pathology 20180929 12


We hypothesized that autophagy and associated lysosome function serve as a critical modulator during Nod-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome activation on proatherogenic stimuli. We first demonstrated that 7-ketocholesterol stimulated Nlrp3 inflammasome formation and activation as shown by increased colocalization of inflammasome components [Nlrp3 versus apoptosis associated speck-like protein (Asc) or caspase-1] and enhanced cleavage of caspase-1 into active casp  ...[more]

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