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

• Published in: JCI insight Vol. 4; no. 21
• Main Authors: Javaheri, Ali, Bajpai, Geetika, Picataggi, Antonino, Mani, Smrithi, Foroughi, Layla, Evie, Hosannah, Kovacs, Attila, Weinheimer, Carla J, Hyrc, Krzystztof, Xiao, Qingli, Ballabio, Andrea, Lee, Jin-Moo, Matkovich, Scot J, Razani, Babak, Schilling, Joel D, Lavine, Kory J, Diwan, Abhinav
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-11-2019
• Subjects: Lysosomes; Inflammation; Cardiology; Macrophages; Autophagy
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.127312

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.