UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis
Jong-Seok Moon, … , Kiichi Nakahira, Augustine M.K. Choi
Jong-Seok Moon, … , Kiichi Nakahira, Augustine M.K. Choi
Published January 9, 2015
Citation Information: J Clin Invest. 2015;125(2):665-680. https://doi.org/10.1172/JCI78253.
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Research Article Immunology

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

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.

Authors

Jong-Seok Moon, Seonmin Lee, Mi-Ae Park, Ilias I. Siempos, Maria Haslip, Patty J. Lee, Mijin Yun, Chun K. Kim, Judie Howrylak, Stefan W. Ryter, Kiichi Nakahira, Augustine M.K. Choi

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Figure 11

Inhibition of FASN activity suppresses production of IL-1β and IL-18 in vivo.

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Inhibition of FASN activity suppresses production of IL-1β and IL-18 in ...
(A) ELISA assay for IL-1β and IL-18 and (B) TG assay in the sera of wild-type mice after injection of C75 (10 mg/kg, i.p.) or DMSO for 16 hours, followed by LPS (10 mg/kg) or PBS for 8 hours. n = 3 per group, *P < 0.05, **P < 0.01, ANOVA. (C) ELISA assay for IL-1β and IL-18 and (D) TG assay in the sera of wild-type mice after injection of cerulenin (5 mg/kg, i.p.) or DMSO for 16 hours, followed by LPS (10 mg/kg) or PBS for 8 hours. n = 3 per group, **P < 0.01, ANOVA. (E) Mice were injected with C75 (10 mg/kg, i.p.) or DMSO. After 16 hours, mice were injected with LPS (10 mg/kg, i.p.) or PBS. Livers were harvested after an additional 8 hours. The image depicts Oil Red O (ORO) staining for neutral lipids and lipid droplet morphology in sections from frozen liver tissues. Scale bar: 100 μm; original magnification, ×40. n = 3 per group, **P < 0.01, ANOVA.