Abstract
Activation of the Nod-like receptor 3 (NLRP3) inflammasome is important for activation of innate immune responses, but improper and excessive activation can cause inflammatory disease. We previously showed that glycolysis, a metabolic pathway that converts glucose into pyruvate, is essential for NLRP3 inflammasome activation in macrophages. Here, we investigated the role of metabolic pathways downstream glycolysis – lactic acid fermentation and pyruvate oxidation—in activation of the NLRP3 inflammasome. Using pharmacological or genetic approaches, we show that decreasing lactic acid fermentation by inhibiting lactate dehydrogenase reduced caspase-1 activation and IL-1β maturation in response to various NLRP3 inflammasome agonists such as nigericin, ATP, monosodium urate (MSU) crystals, or alum, indicating that lactic acid fermentation is required for NLRP3 inflammasome activation. Inhibition of lactate dehydrogenase with GSK2837808A reduced lactate production and activity of the NLRP3 inflammasome regulator, phosphorylated protein kinase R (PKR), but did not reduce the common trigger of NLRP3 inflammasome, potassium efflux, or reactive oxygen species (ROS) production. By contrast, decreasing the activity of pyruvate oxidation by depletion of either mitochondrial pyruvate carrier 2 (MPC2) or pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) enhanced NLRP3 inflammasome activation, suggesting that inhibition of mitochondrial pyruvate transport enhanced lactic acid fermentation. Moreover, treatment with GSK2837808A reduced MSU-mediated peritonitis in mice, a disease model used for studying the consequences of NLRP3 inflammasome activation. Our results suggest that lactic acid fermentation is important for NLRP3 inflammasome activation, while pyruvate oxidation is not. Thus, reprograming pyruvate metabolism in mitochondria and in the cytoplasm should be considered as a novel strategy for the treatment of NLRP3 inflammasome-associated diseases.
Highlights
The Nod-like receptor 3 (NLRP3) inflammasome is a multiprotein complex that is composed of a cytosolic pattern recognition receptor, NLRP3, along with the adaptor protein, apoptosis associated speck-like protein containing a CARD (ASC), and the cysteine-aspartic acid protease-1 [1]
Reports from our group and others showed that glycolysis is essential for NLRP3 inflammasome activation [17,18,19, 26]; we hypothesized that the metabolic pathways downstream from glycolysis—lactic acid fermentation and/or pyruvate oxidation—should be considered in activation of the NLRP3 inflammasome
We found that IL-1β secretion in response to nigericin was significantly inhibited by the glycolysis inhibitor 2-deoxyglucose (2DG) or lactate dehydrogenase (LDH) inhibitor GSK2837808A
Summary
The Nod-like receptor 3 (NLRP3) inflammasome is a multiprotein complex that is composed of a cytosolic pattern recognition receptor, NLRP3, along with the adaptor protein, apoptosis associated speck-like protein containing a CARD (ASC), and the cysteine-aspartic acid protease-1 (caspase-1) [1]. Blocking the electron transport chain increases mitochondrial ROS (mtROS) production This increase of mtROS production is sufficient for activation of the NLRP3 inflammasome, suggesting that mtROS is an activator of the NLRP3 inflammasome [14]. Since glycolysis is branched to pyruvate oxidation-driven OXPHOS in mitochondria or lactic acid fermentation in the cytoplasm, the mechanisms underlying glycolysis-dependent activation of the NLRP3 inflammasome are still poorly understood. In response to cell stimulation with NLRP3 inflammasome agonist, lactic acid fermentation is activated to produce lactate, which induces PKR phosphorylation and activates the NLRP3 inflammasome; which is positively regulated by inhibition of pyruvate oxidation. Our findings provide new insights into the role of pyruvate metabolism in NLRP3 inflammasome activation and suggest that reprogramming of pyruvate metabolism in mitochondria and cytoplasm should be considered as a therapeutic target for treatment of NLRP3 inflammasome-associated diseases
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