RETRACTED ARTICLE: NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages
Open accessAbstract
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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NADPH oxidase 4, responsible for fatty acid oxidation, activates NLRP3 inflammasome in macrophage.
“NADPH oxidase 4, responsible for fatty acid oxidation, activates the NLRP3 inflammasome in macrophage [71].”
From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [71]
Nox4-deficient animals infected with Staphylococcus pneumonia show reduced IL-1β levels in whole lung lysates.
“Nox4-deficient animals infected with Staphylococcus pneumonia showed reduced IL-1β levels in whole lung lysates.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [343]
Location of Nox4 to mitochondria was demonstrated by Western blot analysis of cellular fractions, and Nox4-deficient BMDM show reduced matrix mtROS production after stimulation with LPS and nigericin.
“Location of Nox4 to mitochondria was demonstrated by Western blot analysis of cellular fractions and Nox4-deficient BMDM showed reduced matrix mtROS production after stimulation with LPS and nigericin.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [343]
Nox4-deficient BMDM show reduced fatty acid uptake into mitochondria, reduced fatty acid oxidation, and reduced levels of CPT1.
“Nox4-deficient BMDM also showed reduced fatty acid uptake into mitochondria, reduced fatty acid oxidation and reduced levels of carnitine palmitoyltransferase 1 (CPT1), a key enzyme for fatty acid oxidation.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [343]
WT BMDM treated with LPS/ATP show enhanced expression of Nox4, whereas Nox4-deficient BMDM treated with ATP/LPS show reduced levels of IL-1β and reduced ASC speck formation.
“WT BMDM treated with LPS/ATP showed enhanced expression of Nox4, whereas Nox4-deficient BMDM treated with ATP/LPS showed reduced levels of IL-1β and reduced ASC speck formation.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [343]
In mice, a role for Nox4 in activation of the NLRP3 inflammasome during infection is suggested.
“In contrast to humans, a role for Nox4 in activation of the NLRP3 inflammasome was suggested in mice during infection [343].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [343]
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References 55 · Cited by 291
- Authors
- Moon, J.-S., Nakahira, K., Chung, K.-P., DeNicola, G. M., Koo, M. J., Pabón, M. A., Rooney, K. T., Yoon, J.-H., Ryter, S. W., Stout-Delgado, H., & Choi, A. M. K.
- Affiliations
- NewYork–Presbyterian Hospital (US)
- Yonsei University (KR)
- Corresponding author
- Choi, Augustine M K
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-07-25
- Volume
- 22
- Issue
- 9
- Pages
- 1002-1012
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5204248
- OpenAlex
- W2481644027
- Cited by
- 291
- References
- 55
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 23 · 2023: 38 · 2022: 45 · 2021: 42 · 2020: 37 · 2019: 36 · 2018: 23 · 2017: 32 · 2016: 2
- FWCI
- 16.11
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2023-11-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Aging (R21AG044755, K01AG034999)
- National Heart, Lung, and Blood Institute (R01HL055330, R01HL132198, R01HL079904, P01HL108801, P01HL114501)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- NOX4, fatty acid oxidation, NLRP3 inflammasome, macrophages, CPT1A, mitochondrial metabolism, innate immunity, caspase-1 activation, IL-1β, IL-18, pneumococcal infection, GKT137831, retracted article
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, NADPH Oxidase 4, Animals, Benzoxazoles, Calcium-Binding Proteins, Carnitine O-Palmitoyltransferase, DNA-Binding Proteins, Fatty Acids, Humans, Lipopolysaccharides, Macrophages, Oxidation-Reduction, Pyrazoles, Pyridines, Pyridones, Streptococcal Infections, Streptococcus pneumoniae, Triazoles, Immunoblotting, Cytokines, Mice, Knockout, NADPH Oxidases, Pyrazolones, Adaptor Proteins, Signal Transducing, Lipid Metabolism, Apoptosis Regulatory Proteins, Mice, Metabolomics, Inflammasomes, Real-Time Polymerase Chain Reaction
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