Cited by 238Inflammasome and immune disordersImmune Response and InflammationCancer, Lipids, and Metabolism

UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis

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Moon, Jong-Seok, Lee, Seonmin, Park, Mi-Ae, Siempos, Ilias I., Haslip, Maria, Lee, Patty J., Yun, Mijin, Kim, Chun K. +4 more·2015·Journal of Clinical Investigation

Abstract

Cellular lipid metabolism has been linked to immune responses; however, the precise mechanisms by which de novo fatty acid synthesis can regulate inflammatory responses remain unclear. The NLRP3 inflammasome serves as a platform for caspase-1-dependent maturation and secretion of proinflammatory cytokines. Here, we demonstrated that the mitochondrial uncoupling protein-2 (UCP2) regulates NLRP3-mediated caspase-1 activation through the stimulation of lipid synthesis in macrophages. UCP2-deficient mice displayed improved survival in a mouse model of polymicrobial sepsis. Moreover, UCP2 expression was increased in human sepsis. Consistently, UCP2-deficient mice displayed impaired lipid synthesis and decreased production of IL-1β and IL-18 in response to LPS challenge. In macrophages, UCP2 deficiency suppressed NLRP3-mediated caspase-1 activation and NLRP3 expression associated with inhibition of lipid synthesis. In UCP2-deficient macrophages, inhibition of lipid synthesis resulted from the downregulation of fatty acid synthase (FASN), a key regulator of fatty acid synthesis. FASN inhibition by shRNA and treatment with the chemical inhibitors C75 and cerulenin suppressed NLRP3-mediated caspase-1 activation and inhibited NLRP3 and pro-IL-1β gene expression in macrophages. In conclusion, our results suggest that UCP2 regulates the NLRP3 inflammasome by inducing the lipid synthesis pathway in macrophages. These results identify UCP2 as a potential therapeutic target in inflammatory diseases such as sepsis.

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Crossref · 10.1172/jci78253This paper is marked retracted.

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Authors
Moon, J.-S., Lee, S., Park, M.-A., Siempos, I. I., Haslip, M., Lee, P. J., Yun, M., Kim, C. K., Howrylak, J., Ryter, S. W., Nakahira, K., & Choi, A. M. K.
Affiliations
  • NewYork–Presbyterian Hospital (US)
  • Brigham and Women's Hospital (US)
  • Yale University (US)
  • Pennsylvania State University (US)
Venue
Journal of Clinical Investigation
Published
2015-01-09
Volume
125
Issue
2
Pages
665-680
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2064173000
Cited by
238
References
70
Citations by year
2026: 1 · 2025: 7 · 2024: 16 · 2023: 23 · 2022: 26 · 2021: 33 · 2020: 32 · 2019: 24 · 2018: 24 · 2017: 28 · 2016: 15 · 2015: 9
FWCI
11.01
Type
journal article
Language
en
Status
Retracted
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Strong
  • European Society of Intensive Care Medicine
  • National Institutes of Health
  • College of Veterinary Medicine, Cornell University
  • Weill Cornell Medical College
  • National Heart, Lung, and Blood Institute (R01HL055330, R01HL079904, P01HL108801, R01HL060234, R01HL112747, 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 › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
UCP2, fatty acid synthase, NLRP3 inflammasome, sepsis, macrophages, lipid metabolism, caspase-1 activation, IL-1β, IL-18, lipopolysaccharide, mitochondrial uncoupling, cerulenin, C75, therapeutic target
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Uncoupling Protein 2, Animals, Carrier Proteins, Enzyme Induction, Humans, Ion Channels, Lipids, Macrophages, Down-Regulation, Mice, Knockout, Sepsis, Caspase 1, Interleukin-18, Mitochondrial Proteins, Mice, Interleukin-1beta, Fatty Acid Synthase, Type I, Inflammasomes

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