Dataset Information

MTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation.

ABSTRACT: The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represents a critical metabolic pathway for NLRP3 inflammasome activation. Downregulation of glycolysis by inhibition of Raptor/mTORC1 or HK1 suppressed both pro-IL-1? maturation and caspase-1 activation in macrophages in response to LPS and ATP. These results suggest that upregulation of HK1-dependent glycolysis by mTORC1 regulates NLRP3 inflammasome activation.

SUBMITTER: Moon JS

PROVIDER: S-EPMC4858438 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation.

Moon Jong-Seok JS Hisata Shu S Park Mi-Ae MA DeNicola Gina M GM Ryter Stefan W SW Nakahira Kiichi K Choi Augustine M K AMK

Cell reports 20150625 1

The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represen ...[more]

PMID: 26119735

Similar Datasets

Project description:BackgroundPersistent inflammation dysregulation and cognitive decline have been associated with several trauma- and stress-related disorders such as posttraumatic stress disorder (PTSD) and anxiety disorder. Despite the abundant discoveries of neuroinflammation in such disorders, the underlying mechanisms still remain unclear.MethodWild-type and Nlrp3-/- mice were exposed to the electric foot shocks in the contextual fear memory paradigm. Three hours after the electric foot shocks, activation of the NLRP3 inflammasome was investigated through immunoblotting and ELISA. Microglia were isolated and analyzed by quantitative real-time PCR. Hippocampal tissues were collected 3 h and 72 h after the electric foot shocks and subjected to RNA sequencing. MCC950 was administrated to mice via intraperitoneal (i.p.) injection. Interleukin-1 receptor antagonist (IL-ra) and interleukin-1β (IL-1β) were delivered via intracerebroventricular (i.c.v.) infusion. Contextual fear responses of mice were tested on 4 consecutive days (test days 1-4) starting at 48 h after the electric foot shocks. Anxiety-like behaviors were examined by elevated plus maze and open-field test.ResultsWe demonstrated that, in the contextual fear memory paradigm, the NLRP3 inflammasome was activated 3 h after electric foot shocks. We also found an upregulation in toll-like receptor and RIG-I-like receptor signaling, and a decrease in postsynaptic density (PSD) related proteins, such as PSD95 and Shank proteins, in the hippocampus 72 h after the electric foot shocks, indicating an association between neuroinflammation and PSD protein loss after stress encounter. Meanwhile, Nlrp3 knockout could significantly prevent both neuroinflammation and loss of PSD-related proteins, suggesting a possible protective role of NLRP3 deletion during this process. For further studies, we demonstrated that both genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome remarkably enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior caused by electric foot shocks. Moreover, cytokine IL-1β administration inhibited the extinction of contextual fear memory. Meanwhile, IL-1ra significantly enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior.ConclusionTaken together, our data revealed the pivotal role of NLRP3 inflammasome activation in the regulation of fear memory and the development of PTSD and anxiety disorder, providing a novel target for the clinical treatment of such disorders.

Dataset Information

MTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation.

Publications

mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets