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UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis
- Source :
- Journal of Clinical Investigation. 133
- Publication Year :
- 2023
- Publisher :
- American Society for Clinical Investigation, 2023.
-
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.
- Subjects :
- Inflammasomes
Interleukin-1beta
Caspase 1
Down-Regulation
Biology
Ion Channels
Proinflammatory cytokine
Mitochondrial Proteins
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Sepsis
NLR Family, Pyrin Domain-Containing 3 Protein
medicine
Animals
Humans
Uncoupling Protein 2
Lipid Synthesis Pathway
Fatty acid synthesis
030304 developmental biology
Mice, Knockout
0303 health sciences
integumentary system
Macrophages
Interleukin-18
Lipid metabolism
Inflammasome
General Medicine
Lipids
Cerulenin
Cell biology
Fatty Acid Synthase, Type I
Fatty acid synthase
Biochemistry
chemistry
030220 oncology & carcinogenesis
Enzyme Induction
biology.protein
Carrier Proteins
medicine.drug
Research Article
Subjects
Details
- ISSN :
- 15588238
- Volume :
- 133
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....9632ffd7e04030d4fbaad1f96f28b3dd