Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation

Area of Science:

• Immunology
• Metabolism
• Cell Biology

Background:

• The Nod-like receptor 3 (NLRP3) inflammasome is vital for innate immunity but its overactivation causes inflammatory diseases.
• Glycolysis, the initial breakdown of glucose, is a known prerequisite for NLRP3 inflammasome activation in macrophages.

Purpose of the Study:

• To investigate the roles of lactic acid fermentation and pyruvate oxidation, metabolic pathways following glycolysis, in NLRP3 inflammasome activation.

Main Methods:

• Pharmacological inhibition of lactate dehydrogenase (LDH) using GSK2837808A.
• Genetic depletion of mitochondrial pyruvate carrier 2 (MPC2) or pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1).
• Assessment of caspase-1 activation, IL-1β maturation, lactate production, phosphorylated protein kinase R (pPKR) activity, potassium efflux, reactive oxygen species (ROS) production, and MSU-mediated peritonitis in mice.

Main Results:

• Inhibition of lactic acid fermentation via LDH reduction decreased caspase-1 activation and IL-1β maturation, indicating its necessity for NLRP3 inflammasome activation.
• LDH inhibition reduced lactate production and pPKR activity but did not affect potassium efflux or ROS production.
• Inhibition of pyruvate oxidation (MPC2 or PDHA1 depletion) enhanced NLRP3 inflammasome activation, suggesting increased lactic acid fermentation.
• GSK2837808A treatment attenuated MSU-induced peritonitis in a mouse model.

Conclusions:

• Lactic acid fermentation is essential for NLRP3 inflammasome activation, whereas pyruvate oxidation is not.
• Targeting pyruvate metabolism, specifically promoting lactic acid fermentation, presents a novel therapeutic strategy for NLRP3 inflammasome-associated inflammatory diseases.