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Nat Med. 2016 Sep;22(9):1002-12. doi: 10.1038/nm.4153. Epub 2016 Jul 25.

NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages.

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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.
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.


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.

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