{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T04:06:57Z","timestamp":1794024417661,"version":"4.8.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 \u2013 lactic acid fermentation and pyruvate oxidation\u2014in 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-1\u03b2 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.<\/jats:p>","DOI":"10.3389\/fimmu.2021.630380","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T04:44:08Z","timestamp":1616993048000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":62,"title":["Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation"],"prefix":"10.3389","volume":"12","author":[{"given":"Hsin-Chung","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Jen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yau-Huei","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-An","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Chou","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tze-Fan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Lin","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Yang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hung","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsueh-Hsiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lih-Chyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/nri.2016.58","article-title":"Inflammasomes: mechanism of assembly, regulation and signalling","volume":"16","author":"Broz","year":"2016","journal-title":"Nat Rev Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1016\/j.cell.2014.02.008","article-title":"Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes","volume":"156","author":"Lu","year":"2014","journal-title":"Cell."},{"key":"B3","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/nature04516","article-title":"Gout-associated uric acid crystals activate the NALP3 inflammasome","volume":"440","author":"Martinon","year":"2006","journal-title":"Nature."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1016\/j.immuni.2013.05.016","article-title":"K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter","volume":"38","author":"Munoz-Planillo","year":"2013","journal-title":"Immunity."},{"key":"B5","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fmicb.2011.00012","article-title":"Role of the nlrp3 inflammasome in microbial infection","volume":"2","author":"Anand","year":"2011","journal-title":"Front Microbiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"194","DOI":"10.2337\/db12-0420","article-title":"Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes","volume":"62","author":"Lee","year":"2013","journal-title":"Diabetes."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1161\/CIRCRESAHA.118.311362","article-title":"NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis","volume":"122","author":"Grebe","year":"2018","journal-title":"Circ Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1136\/annrheumdis-2013-203276","article-title":"Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment","volume":"73","author":"Mathews","year":"2014","journal-title":"Ann Rheum Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1164\/rccm.201604-0892OC","article-title":"NLRP3 Inflammasome deficiency protects against microbial sepsis via increased lipoxin B4 synthesis","volume":"196","author":"Lee","year":"2017","journal-title":"Am J Respir Crit Care Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.jaut.2018.03.002","article-title":"Gain of function mutation and inflammasome driven diseases in human and mouse models","volume":"91","author":"Cordero","year":"2018","journal-title":"J Autoimmun"},{"key":"B11","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nature11729","article-title":"NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP\/PS1 mice","volume":"493","author":"Heneka","year":"2013","journal-title":"Nature."},{"key":"B12","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/s12943-018-0900-3","article-title":"Role of the NLRP3 inflammasome in cancer","volume":"17","author":"Moossavi","year":"2018","journal-title":"Mol Cancer."},{"key":"B13","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome, molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat Rev Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/nature09663","article-title":"A role for mitochondria in NLRP3 inflammasome activation","volume":"469","author":"Zhou","year":"2011","journal-title":"Nature."},{"key":"B15","doi-asserted-by":"publisher","first-page":"5230","DOI":"10.4049\/jimmunol.1301490","article-title":"Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation","volume":"191","author":"Heid","year":"2013","journal-title":"J Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1038\/sj.cdd.4402195","article-title":"Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration","volume":"14","author":"Petrilli","year":"2007","journal-title":"Cell Death Differ."},{"key":"B17","doi-asserted-by":"publisher","first-page":"5104","DOI":"10.3390\/ijms21145104","article-title":"Cbl Negatively Regulates NLRP3 Inflammasome Activation through GLUT1-Dependent Glycolysis Inhibition","volume":"21","author":"Lin","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.celrep.2015.05.046","article-title":"mTORC1-Induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation","volume":"12","author":"Moon","year":"2015","journal-title":"Cell Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"13280","DOI":"10.1038\/ncomms13280","article-title":"PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation","volume":"7","author":"Xie","year":"2016","journal-title":"Nat Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/nature11290","article-title":"Novel role of PKR in inflammasome activation and HMGB1 release","volume":"488","author":"Lu","year":"2012","journal-title":"Nature."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1038\/s41419-018-1163-z","article-title":"Src-family kinase-Cbl axis negatively regulates NLRP3 inflammasome activation","volume":"9","author":"Chung","year":"2018","journal-title":"Cell Death Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1074\/mcp.M112.020594","article-title":"Interactome-wide analysis identifies end-binding protein 1 as a crucial component for the speck-like particle formation of activated absence in melanoma 2 (AIM2) inflammasomes","volume":"11","author":"Wang","year":"2012","journal-title":"Mol Cell Proteomics."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1002\/emmm.201201569","article-title":"Tumour inflammasome-derived IL-1beta recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma","volume":"4","author":"Chen","year":"2012","journal-title":"EMBO Mol Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"455","DOI":"10.4049\/jimmunol.1401110","article-title":"A novel flow cytometric method to assess inflammasome formation","volume":"194","author":"Sester","year":"2015","journal-title":"J Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"516","DOI":"10.3390\/nu11030516","article-title":"Pretreatment with a heat-killed probiotic modulates the NLRP3 inflammasome and attenuates colitis-associated colorectal cancer in mice","volume":"11","author":"Chung","year":"2019","journal-title":"Nutrients"},{"key":"B26","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/ni.3659","article-title":"Postprandial macrophage-derived IL-1beta stimulates insulin, and both synergistically promote glucose disposal and inflammation","volume":"18","author":"Dror","year":"2017","journal-title":"Nat Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1042\/BJ20141171","article-title":"Mitochondrial pyruvate transport, a historical perspective and future research directions","volume":"466","author":"McCommis","year":"2015","journal-title":"Biochem J."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1038\/ni.2749","article-title":"Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity","volume":"14","author":"Hara","year":"2013","journal-title":"Nat Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"36214","DOI":"10.1038\/srep36214","article-title":"Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis","volume":"6","author":"Chung","year":"2016","journal-title":"Sci Rep."},{"key":"B30","doi-asserted-by":"publisher","first-page":"7884","DOI":"10.1074\/jbc.M113.522037","article-title":"Metabolic reprogramming of macrophages, glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype","volume":"289","author":"Freemerman","year":"2014","journal-title":"J Biol Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1126\/science.1218099","article-title":"A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans","volume":"337","author":"Bricker","year":"2012","journal-title":"Science."},{"key":"B32","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/s1096-7192(03)00016-7","article-title":"Impaired mitochondrial pyruvate importation in a patient and a fetus at risk","volume":"78","author":"Brivet","year":"2003","journal-title":"Mol Genet Metab."},{"key":"B33","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.molcel.2014.01.016","article-title":"Regulation of autophagy by cytosolic acetyl-coenzyme A","volume":"53","author":"Marino","year":"2014","journal-title":"Mol Cell."},{"key":"B34","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1038\/ni.1831","article-title":"Thioredoxin-interacting protein links oxidative stress to inflammasome activation","volume":"11","author":"Zhou","year":"2010","journal-title":"Nat Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.3389\/fimmu.2020.01444","article-title":"NLRP3 inflammasome activation in cancer: a double-edged sword","volume":"11","author":"Hamarsheh","year":"2020","journal-title":"Front Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"50074","DOI":"10.18632\/oncotarget.10317","article-title":"ASC contributes to metastasis of oral cavity squamous cell carcinoma","volume":"7","author":"Wu","year":"2016","journal-title":"Oncotarget."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1073\/pnas.1812266115","article-title":"Blocking IL-1beta reverses the immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor abrogation","volume":"116","author":"Kaplanov Carmi","year":"2019","journal-title":"Proc Natl Acad Sci USA."},{"key":"B39","doi-asserted-by":"publisher","first-page":"36107","DOI":"10.1038\/srep36107","article-title":"Targeting inflammasome\/IL-1 pathways for cancer immunotherapy","volume":"6","author":"Guo","year":"2016","journal-title":"Sci Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1084\/jem.20160392","article-title":"S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3\/IL-1beta","volume":"214","author":"Weichand","year":"2017","journal-title":"J Exp Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/iub.573","article-title":"The monocarboxylate transporter family\u2014structure and functional characterization","volume":"64","author":"Halestrap","year":"2012","journal-title":"IUBMB Life."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/j.cell.2015.08.016","article-title":"Metabolic competition in the tumor microenvironment is a driver of cancer progression","volume":"162","author":"Chang","year":"2015","journal-title":"Cell."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.cell.2015.08.012","article-title":"Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses","volume":"162","author":"Ho","year":"2015","journal-title":"Cell."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e99735","DOI":"10.15252\/embj.201899735","article-title":"Targeting the warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival","volume":"37","author":"Pathria","year":"2018","journal-title":"EMBO J"},{"key":"B45","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.cmet.2018.02.024","article-title":"Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy","volume":"27","author":"Cascone","year":"2018","journal-title":"Cell Metab."}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.630380\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T04:44:09Z","timestamp":1616993049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.630380\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2021.630380"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.630380","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]},"article-number":"630380"}}