PMID- 27455510 OWN - NLM STAT- MEDLINE DCOM- 20170810 LR - 20231124 IS - 1546-170X (Electronic) IS - 1078-8956 (Print) IS - 1078-8956 (Linking) VI - 22 IP - 9 DP - 2016 Sep TI - NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. PG - 1002-12 LID - 10.1038/nm.4153 [doi] AB - Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1beta and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation. FAU - Moon, Jong-Seok AU - Moon JS AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Nakahira, Kiichi AU - Nakahira K AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Chung, Kuei-Pin AU - Chung KP AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. AD - Department of Laboratory Medicine, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan, China. FAU - DeNicola, Gina M AU - DeNicola GM AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. FAU - Koo, Michael Jakun AU - Koo MJ AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Pabon, Maria A AU - Pabon MA AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. FAU - Rooney, Kristen T AU - Rooney KT AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Yoon, Joo-Heon AU - Yoon JH AUID- ORCID: 0000-0003-2404-7156 AD - Research Center for Natural Human Defense System, Yonsei University College of Medicine, Seoul, Republic of Korea. AD - Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea. AD - The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, South Korea. FAU - Ryter, Stefan W AU - Ryter SW AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Stout-Delgado, Heather AU - Stout-Delgado H AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Choi, Augustine M K AU - Choi AM AD - Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA. AD - Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA. LA - eng GR - P01 HL108801/HL/NHLBI NIH HHS/United States GR - R21 AG044755/AG/NIA NIH HHS/United States GR - K01 AG034999/AG/NIA NIH HHS/United States GR - R01 HL132198/HL/NHLBI NIH HHS/United States GR - R01 HL055330/HL/NHLBI NIH HHS/United States GR - R01 HL079904/HL/NHLBI NIH HHS/United States GR - P01 HL114501/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Retracted Publication DEP - 20160725 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Aim2 protein, mouse) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Benzoxazoles) RN - 0 (Calcium-Binding Proteins) RN - 0 (Cytokines) RN - 0 (DNA-Binding Proteins) RN - 0 (Fatty Acids) RN - 0 (Inflammasomes) RN - 0 (Ipaf protein, mouse) RN - 0 (Lipopolysaccharides) RN - 0 (NALP1 protein, mouse) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRP3 protein, human) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Pyrazoles) RN - 0 (Pyrazolones) RN - 0 (Pyridines) RN - 0 (Pyridones) RN - 0 (Triazoles) RN - 45II35329V (setanaxib) RN - EC 1.6.3.- (NADPH Oxidase 4) RN - EC 1.6.3.- (NADPH Oxidases) RN - EC 1.6.3.- (Nox4 protein, mouse) RN - EC 2.3.1.21 (CPT1B protein, mouse) RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) SB - IM RIN - Nat Med. 2023 Dec;29(12):3272. PMID: 38001272 MH - Adaptor Proteins, Signal Transducing/immunology/metabolism MH - Animals MH - Apoptosis Regulatory Proteins/immunology/metabolism MH - Benzoxazoles/pharmacology MH - Calcium-Binding Proteins/immunology/metabolism MH - Carnitine O-Palmitoyltransferase/genetics/metabolism MH - Cytokines/immunology MH - DNA-Binding Proteins/immunology/metabolism MH - Fatty Acids/*metabolism MH - Humans MH - Immunoblotting MH - Inflammasomes/immunology MH - Lipid Metabolism/drug effects/*immunology MH - Lipopolysaccharides/pharmacology MH - Macrophages/drug effects/*immunology/metabolism MH - Metabolomics MH - Mice MH - Mice, Knockout MH - NADPH Oxidase 4 MH - NADPH Oxidases/antagonists & inhibitors/*genetics MH - NLR Family, Pyrin Domain-Containing 3 Protein/*immunology/metabolism MH - Oxidation-Reduction MH - Pyrazoles/pharmacology MH - Pyrazolones MH - Pyridines/pharmacology MH - Pyridones MH - Real-Time Polymerase Chain Reaction MH - Streptococcal Infections/immunology MH - Streptococcus pneumoniae MH - Triazoles/pharmacology PMC - PMC5204248 MID - NIHMS834041 EDAT- 2016/07/28 06:00 MHDA- 2017/08/11 06:00 PMCR- 2017/01/02 CRDT- 2016/07/26 06:00 PHST- 2016/04/06 00:00 [received] PHST- 2016/06/22 00:00 [accepted] PHST- 2016/07/26 06:00 [entrez] PHST- 2016/07/28 06:00 [pubmed] PHST- 2017/08/11 06:00 [medline] PHST- 2017/01/02 00:00 [pmc-release] AID - nm.4153 [pii] AID - 10.1038/nm.4153 [doi] PST - ppublish SO - Nat Med. 2016 Sep;22(9):1002-12. doi: 10.1038/nm.4153. Epub 2016 Jul 25.