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UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during 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 
Citation
 Journal of Clinical Investigation, Vol.125(2) : 665-680, 2015 
Journal Title
 Journal of Clinical Investigation 
ISSN
 0021-9738 
Issue Date
2015
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.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141470
DOI
10.1172/JCI78253
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실)
Yonsei Authors
윤미진(Yun, Mi Jin)
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