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Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation

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 NLR...

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Autores principales: Lin, Hsin-Chung, Chen, Yu-Jen, Wei, Yau-Huei, Lin, Hsin-An, Chen, Chien-Chou, Liu, Tze-Fan, Hsieh, Yi-Lin, Huang, Kuo-Yang, Lin, Kuan-Hung, Wang, Hsueh-Hsiao, Chen, Lih-Chyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039150/
https://www.ncbi.nlm.nih.gov/pubmed/33854503
http://dx.doi.org/10.3389/fimmu.2021.630380
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author Lin, Hsin-Chung
Chen, Yu-Jen
Wei, Yau-Huei
Lin, Hsin-An
Chen, Chien-Chou
Liu, Tze-Fan
Hsieh, Yi-Lin
Huang, Kuo-Yang
Lin, Kuan-Hung
Wang, Hsueh-Hsiao
Chen, Lih-Chyang
author_facet Lin, Hsin-Chung
Chen, Yu-Jen
Wei, Yau-Huei
Lin, Hsin-An
Chen, Chien-Chou
Liu, Tze-Fan
Hsieh, Yi-Lin
Huang, Kuo-Yang
Lin, Kuan-Hung
Wang, Hsueh-Hsiao
Chen, Lih-Chyang
author_sort Lin, Hsin-Chung
collection PubMed
description 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.
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spelling pubmed-80391502021-04-13 Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation Lin, Hsin-Chung Chen, Yu-Jen Wei, Yau-Huei Lin, Hsin-An Chen, Chien-Chou Liu, Tze-Fan Hsieh, Yi-Lin Huang, Kuo-Yang Lin, Kuan-Hung Wang, Hsueh-Hsiao Chen, Lih-Chyang Front Immunol Immunology 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. Frontiers Media S.A. 2021-03-29 /pmc/articles/PMC8039150/ /pubmed/33854503 http://dx.doi.org/10.3389/fimmu.2021.630380 Text en Copyright © 2021 Lin, Chen, Wei, Lin, Chen, Liu, Hsieh, Huang, Lin, Wang and Chen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Lin, Hsin-Chung
Chen, Yu-Jen
Wei, Yau-Huei
Lin, Hsin-An
Chen, Chien-Chou
Liu, Tze-Fan
Hsieh, Yi-Lin
Huang, Kuo-Yang
Lin, Kuan-Hung
Wang, Hsueh-Hsiao
Chen, Lih-Chyang
Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation
title Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation
title_full Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation
title_fullStr Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation
title_full_unstemmed Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation
title_short Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation
title_sort lactic acid fermentation is required for nlrp3 inflammasome activation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039150/
https://www.ncbi.nlm.nih.gov/pubmed/33854503
http://dx.doi.org/10.3389/fimmu.2021.630380
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