title: NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages.
abstract: 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)-1β 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.
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Moon
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.|Department of Laboratory Medicine, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan, China.
authors.forename: Kuei-Pin
authors.initials: KP
authors.lastname: Chung
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: DeNicola
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Michael Jakun
authors.initials: MJ
authors.lastname: Koo
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pabón
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Kristen T
authors.initials: KT
authors.lastname: Rooney
authors.affiliation: Research Center for Natural Human Defense System, Yonsei University College of Medicine, Seoul, Republic of Korea.|Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea.|The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Joo-Heon
authors.identifier: 0000-0003-2404-7156
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Stout-Delgado
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York, USA.|Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D001583:Benzoxazoles / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D058847:Inflammasomes / Q000276:immunology; D050356:Lipid Metabolism / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology* / Q000378:metabolism; D010084:Oxidation-Reduction; D011720:Pyrazoles / Q000494:pharmacology; D047069:Pyrazolones; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones; D060888:Real-Time Polymerase Chain Reaction; D013290:Streptococcal Infections / Q000276:immunology; D013296:Streptococcus pneumoniae; D014230:Triazoles / Q000494:pharmacology
chemical_list: C511179:3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine; D048868:Adaptor Proteins, Signal Transducing; C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D001583:Benzoxazoles; D002135:Calcium-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D058847:Inflammasomes; C512299:Ipaf protein, mouse; D008070:Lipopolysaccharides; C529636:NALP1 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; D011728:Pyridones; D014230:Triazoles; C576694:setanaxib; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C558401:CPT1B protein, mouse; D002334:Carnitine O-Palmitoyltransferase