한빛사 논문
Jong-Seok Moon1,2, Seonmin Lee3,4, Mi-Ae Park5, Ilias I. Siempos1,2,6, Maria Haslip7, Patty J. Lee7, Mijin Yun3,8, Chun K. Kim5, Judie Howrylak9, Stefan W. Ryter1,2, Kiichi Nakahira1,2 and Augustine M.K. Choi1,2
1Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, and New York-Presbyterian Hospital, New York, New York, USA.
2Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York, USA.
3Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA.
4Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
5Department of Radiology, BWH, Harvard Medical School, Boston, Massachusetts, USA.
6Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens, Greece.
7Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
8Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
9Division of Pulmonary and Critical Care Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA.
*Address correspondence to: Augustine M.K. Choi, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical Center, 525 East 68th Street, Room M-522, Box 130, New York, New York 10065, USA.
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.
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