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.
View: Text | PDF | Retraction
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

×

Figure 6

FASN regulates NLRP3 and IL-1β expression through AKT activation in macrophages.

Options: View larger image (or click on image) Download as PowerPoint
FASN regulates NLRP3 and IL-1β expression through AKT activation in macr...
(A) Immunoblot analysis for NLRP3 and IL-1β and (B) measurement of TGs from wild-type BMDMs pretreated with C75 (0, 10, 20, and 50 μM) as well as (C) measurement of PEP, citrate, and lactate production from wild-type BMDMs pretreated with C75 (20 μM) for 2 hours before stimulation with LPS (500 ng/ml, 4 hours). β-Actin served as the standard. **P < 0.01, ANOVA. (D) Immunoblot analysis of AKT Ser473 phosphorylation in wild-type BMDMs pretreated with C75 (20 μM) for 2 hours before stimulation with LPS (500 ng/ml; 0, 10, and 20 minutes). Total AKT served as the standard. (E) Immunoblot analysis of AKT Ser473 phosphorylation in cell lysates from wild-type BMDMs pretreated with C75 (0, 10, 20, and 50 μM) for 2 hours before stimulation with LPS (500 ng/ml, 4 hours). Total AKT served as the standard. (F) Immunoblot analysis of AKT Ser473 phosphorylation in cell lysates from wild-type peritoneal macrophages transduced with lentiviruses expressing nontarget shRNA or 3 independent shRNA for FASN after stimulation with LPS (500 ng/ml, 4 hours). Total AKT served as the standard. (G) Immunoblot analysis for NLRP3, IL-1β, and AKT Ser473 phosphorylation in cell lysates from wild-type BMDMs pretreated with BX795 (10 μM) for 1 hour before stimulation with LPS (500 ng/ml, 4 hours). Total AKT served as the standard.