TY - JOUR
T1 - TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy
AU - Javaheri, Ali
AU - Bajpai, Geetika
AU - Picataggi, Antonino
AU - Mani, Smrithi
AU - Foroughi, Layla
AU - Evie, Hosannah
AU - Kovacs, Attila
AU - Weinheimer, Carla J.
AU - Hyrc, Krzystztof
AU - Xiao, Qingli
AU - Ballabio, Andrea
AU - Lee, Jin Moo
AU - Matkovich, Scot J.
AU - Razani, Babak
AU - Schilling, Joel D.
AU - Lavine, Kory J.
AU - Diwan, Abhinav
N1 - Publisher Copyright:
© 2019 American Society for Clinical Investigation. All rights reserved.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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 (M-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor M-TFEB mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed "autophagy"). RNA-seq of flow-sorted macrophages postinfarction revealed that M-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-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.
AB - 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 (M-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor M-TFEB mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed "autophagy"). RNA-seq of flow-sorted macrophages postinfarction revealed that M-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-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.
UR - http://www.scopus.com/inward/record.url?scp=85077579000&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.127312
DO - 10.1172/jci.insight.127312
M3 - Article
C2 - 31672943
AN - SCOPUS:85077579000
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 21
M1 - e127312
ER -