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JCI Insight. 2019 Nov 1;4(21). pii: 127312. doi: 10.1172/jci.insight.127312.

TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy.

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Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine.
Alafi Neuroimaging Laboratory, and.
Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, Missouri, USA.
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
John Cochran Veterans Affairs Medical Center, Saint Louis, Missouri, USA.


Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β 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 overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed "autophagy"). RNA-seq of flow-sorted macrophages postinfarction revealed that Mϕ-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 Mϕ-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.


Autophagy; Cardiology; Inflammation; Lysosomes; Macrophages

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