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

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

doi:10.1172/jci78253

Cited by 226 publications

(217 citation statements)

References 69 publications

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“…In contrast, short chain acylcarnitines were relatively decreased in IFN-␥-stimulated Irgm1-deficient BMM. Because LC-AC have pro-inflammatory properties (47)(48)(49)(50)(51), these data reinforce the finding that in IFN-␥-primed Irgm1-deficient macrophages, metabolic changes occur that are proinflammatory and typically only seen in macrophages following activation with LPS. We also exposed the cells to LPS and IFN-␥ to examine how the metabolic changes in IFN-␥-primed, Irgm1-deficient cells might compare with those in fully activated macrophages.…”

Section: Resultssupporting

confidence: 76%

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-␥ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-␥-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.

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Section: Resultssupporting

confidence: 76%

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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show abstract

“…Importantly, UCP-2-deficient mice showed improved survival after polymicrobial sepsis and decreased lipid synthesis and secretion of IL-1b and IL-18 after LPS challenge. 66 Considerable efforts have focused on identifying agonists of NLRP3 inflammasome activation as well as determining the molecular mechanisms by which diverse agonists induce the assembly of inflammasome components.…”

Section: Pamp Signals That Activate the Nlrp3 Inflammasomementioning

confidence: 99%

Molecular mechanisms regulating NLRP3 inflammasome activation

et al. 2015

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“…Recent work has demonstrated that functional FASN is essential for inflammasome priming in mouse peritoneal macrophages in response to LPS [40] . The authors demonstrated, through pharmacological and genetic approaches, that loss of function of FASN reduced NLRP3 induction in response to inflammatory stimuli, and that inhibition of FASN decreased IL-1 and IL-18 levels in serum of mice during LPS challenge.…”

Section: Inflammasome Priming Via Lipid Metabolismmentioning

confidence: 99%

“…Downstream, FASN facilitated the inflammatory signal by promoting the phosphorylation of AKT; however, the kinase through which FASN might coordinate phosphorylation was not identified [40] . Activation of this kinase might occur through a regulatory lipid, downstream of FASN, or perhaps FASN might harbor an alternative novel enzymatic function.…”

Section: Inflammasome Priming Via Lipid Metabolismmentioning

confidence: 99%