Journal
AUTOPHAGY
Volume 18, Issue 6, Pages 1385-1400Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2021.1985338
Keywords
AMPK; FLT4; VEGFR3; glycolytic reprogramming; inflammasome; pyroptosis
Categories
Funding
- Ministry of Science and Technology of the People's Republic of China [2016YFD0500407, 2016YFC0905902, 2018YFA0800702, 2016YFD0500207, 2016YFC0905900]
- National Natural Science Foundation of China [81930038, 81825011, 81630043, 81671572, 81571552, 81701569, 31700781, 81801575, 30671038, 81961160738]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB19000000]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Hundred Talents Program of the Chinese Academy of Sciences
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Macrophages undergo glycolytic reprogramming, autophagy, inflammasome activation, and pyroptosis to eliminate invading bacteria. The FLT4-AMPK module plays a crucial role in coordinating these processes, with potential therapeutic applications.
Macrophages rapidly undergo glycolytic reprogramming in response to macroautophagy/autophagy, inflammasome activation and pyroptosis for the clearance of bacteria. Identification the key molecules involved in these three events will provide critical potential therapeutic applications. Upon S. typhimurium infection, FLT4/VEGFR3 and its ligand VEGFC were inducibly expressed in macrophages, and FLT4 signaling inhibited CASP1 (caspase 1)-dependent inflammasome activation and pyroptosis but enhanced MAP1LC3/LC3 activation for elimination of the bacteria. Consistently, FLT4 mutants lacking the extracellular ligand-binding domain increased production of the proinflammatory metabolites such as succinate and lactate, and reduced antimicrobial metabolites including citrate and NAD(P)H in macrophages and liver upon infection. Mechanistically, FLT4 recruited AMP-activated protein kinase (AMPK) and phosphorylated Y247 and Y441/442 in the PRKAA/alpha subunit for AMPK activation. The AMPK agonist AICAR could rescue glycolytic reprogramming and inflammasome activation in macrophages expressing the mutant FLT4, which has potential translational application in patients carrying Flt4 mutations to prevent recurrent infections. Collectively, we have elucidated that the FLT4-AMPK module in macrophages coordinates glycolytic reprogramming, autophagy, inflammasome activation and pyroptosis to eliminate invading bacteria.
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