期刊
JCI INSIGHT
卷 4, 期 21, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.127312
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资金
- Department of Veterans Affairs [I01BX004235]
- NIH [HL107594]
- NHLBI [5-T32-HL007081, K08-HL138262]
- Diabetes Research Center at Washington University in St. Louis of the NIH [P30DK020579]
- NIH Shared Instrumentation Grant through the Hope Center Neuroimaging Core [S10 RR027552]
- Advanced Imaging and Tissue Analysis Core of the Digestive Disease Research Core Center at Washington University School of Medicine [DDRCC NIH P30DK052574]
Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1 beta secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpress ion of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (M phi-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1 beta compared with controls. Surprisingly, neither inflammasome suppression nor M phi-TFEB-mediated attenuation of postinfarction myocardial dysfunction required intact ATGS-dependent macroautophagy (hereafter termed autophagy). RNA-seq of flow-sorted macrophages postinfarction revealed that M phi-TFEB upregulated key targets involved in lysosomal lipid metabolism. Specifically, inhibition of the TFEB target, lysosomal acid lipase, in vivo abrogated the beneficial effect of M phi-TFEB on postinfarction ventricular function. Thus, TFEB reprograms macrophage lysosomal lipid metabolism to attenuate remodeling after IR, suggesting an alternative paradigm whereby lysosome function affects inflammation.
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