Journal Article

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

Stout-Delgado, Heather, Nakahira, Kiichi, Rooney, Kristen T, Koo, Michael Jakun, Chung, Kuei-Pin, DeNicola, Gina M, Pabón, Maria A, Choi, Augustine M K, Ryter, Stefan W, Yoon, Joo-Heon, Moon, Jong-Seok

2016

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Adaptor Proteins, Signal Transducing - immunology / Adaptor Proteins, Signal Transducing - metabolism / Animals / Anions / Apoptosis Regulatory Proteins - immunology / Apoptosis Regulatory Proteins - metabolism / Benzoxazoles - pharmacology / Calcium-Binding Proteins - immunology / Calcium-Binding Proteins - metabolism / Carnitine O-Palmitoyltransferase - genetics / Carnitine O-Palmitoyltransferase - metabolism / Cells / Cellular signal transduction / Cytokines - immunology / DNA-Binding Proteins - immunology / DNA-Binding Proteins - metabolism / Enzyme activation / Fatty acids / Fatty Acids - metabolism / Genetic aspects / Health aspects / Humans / Immune response / Immunoblotting / Inflammasomes / Inflammasomes - immunology / Lipid Metabolism - drug effects / Lipid Metabolism - immunology / Lipopolysaccharides - pharmacology / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Melanoma / Metabolic disorders / Metabolism / Metabolomics / Mice / Mice, Knockout / NADPH Oxidase 4 / NADPH Oxidases - antagonists & inhibitors / NADPH Oxidases - genetics / NLR Family, Pyrin Domain-Containing 3 Protein - immunology / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Oxidases / Oxidation / Oxidation-Reduction / Properties / Pyrazoles - pharmacology / Pyridines - pharmacology / Real-Time Polymerase Chain Reaction / Streptococcal Infections - immunology / Streptococcus pneumoniae / Transferases / Triazoles - pharmacology