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FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for

Li Ma1, Weiyun Li1,2, Yanbo Zhang1,3

  • 1State Key Laboratory of Cell Biology, Cas Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Autophagy
|October 11, 2021
PubMed

Insights

The FLT4-AMPK pathway in macrophages is crucial for bacterial clearance, coordinating autophagy and inflammasome activation. This finding offers therapeutic potential for infections linked to Flt4 mutations.

Area of Science:

  • Immunology
  • Cellular Metabolism
  • Microbiology

Background:

  • Macrophages employ glycolytic reprogramming, autophagy, inflammasome activation, and pyroptosis to clear bacterial infections.
  • Understanding the molecular players governing these interconnected processes is vital for developing novel therapeutic strategies.

Purpose of the Study:

  • To elucidate the role of the FLT4 receptor tyrosine kinase and its ligand VEGFC in macrophage response to bacterial infection.
  • To investigate the molecular mechanisms by which FLT4 signaling influences bacterial clearance, metabolic reprogramming, and inflammatory responses.

Main Methods:

  • Investigated FLT4/VEGFR3 and VEGFC expression in macrophages during *S. typhimurium* infection.
  • Analyzed the impact of FLT4 signaling on inflammasome activation (CASP1), pyroptosis, and autophagy (MAP1LC3/LC3).
  • Assessed metabolic profiles (lactate, succinate, citrate, NAD(P)H) in wild-type and FLT4-mutant macrophages and livers.
  • Determined the role of AMP-activated protein kinase (AMPK) in FLT4-mediated signaling and bacterial clearance.

Main Results:

  • FLT4 signaling inhibited caspase 1-dependent inflammasome activation and pyroptosis while promoting autophagy for bacterial elimination.
  • FLT4 mutants exhibited dysregulated glycolytic reprogramming, characterized by increased pro-inflammatory metabolites and decreased antimicrobial metabolites.
  • FLT4 recruited and activated AMPK, which was essential for its protective functions against bacterial infection.
  • The AMPK agonist AICAR rescued metabolic and inflammatory defects in FLT4-mutant macrophages.

Conclusions:

  • The FLT4-AMPK signaling module in macrophages is a key regulator coordinating glycolytic reprogramming, autophagy, inflammasome activation, and pyroptosis for effective bacterial clearance.
  • Targeting the FLT4-AMPK pathway presents a potential therapeutic avenue for managing bacterial infections, particularly in individuals with *Flt4* mutations.
Keywords:
AMPKFLT4/VEGFR3glycolytic reprogramminginflammasomepyroptosis

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