title: 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.forename: Jong-Seok
authors.initials: JS
authors.lastname: Moon
authors.forename: Seonmin
authors.initials: S
authors.lastname: Lee
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Park
authors.forename: Ilias I
authors.initials: II
authors.lastname: Siempos
authors.forename: Maria
authors.initials: M
authors.lastname: Haslip
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
authors.forename: Mijin
authors.initials: M
authors.lastname: Yun
authors.forename: Chun K
authors.initials: CK
authors.lastname: Kim
authors.forename: Judie
authors.initials: J
authors.lastname: Howrylak
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004790:Enzyme Induction / Q000235:genetics; D054890:Fatty Acid Synthase, Type I / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000071246:Uncoupling Protein 2
chemical_list: D002352:Carrier Proteins; C000594089:IL1B protein, rat; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D007473:Ion Channels; D008055:Lipids; D024101:Mitochondrial Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D054890:Fatty Acid Synthase, Type I; D020170:Caspase 1