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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.

Author information

1
Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine.
2
Alafi Neuroimaging Laboratory, and.
3
Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, Missouri, USA.
4
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
5
Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy.
6
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
8
John Cochran Veterans Affairs Medical Center, Saint Louis, Missouri, USA.

Abstract

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.

KEYWORDS:

Autophagy; Cardiology; Inflammation; Lysosomes; Macrophages

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