title: Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death.
abstract: When innate immune cells such as macrophages are challenged with environmental stresses or infection by pathogens, they trigger the rapid assembly of multi-protein complexes called inflammasomes that are responsible for initiating pro-inflammatory responses and a form of cell death termed pyroptosis. We describe here the identification of an intracellular trigger of NLRP3-mediated inflammatory signaling, IL-1β production and pyroptosis in primed murine bone marrow-derived macrophages that is mediated by the disruption of glycolytic flux. This signal results from a drop of NADH levels and induction of mitochondrial ROS production and can be rescued by addition of products that restore NADH production. This signal is also important for host-cell response to the intracellular pathogen Salmonella typhimurium, which can disrupt metabolism by uptake of host-cell glucose. These results reveal an important inflammatory signaling network used by immune cells to sense metabolic dysfunction or infection by intracellular pathogens.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Sanman
authors.affiliation: Department of Chemistry, Boston College, Chestnut Hill, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Eisele
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Tessie M
authors.initials: TM
authors.lastname: Ng
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Wouter A
authors.initials: WA
authors.lastname: van der Linden
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Monack
authors.affiliation: Department of Chemistry, Boston College, Chestnut Hill, United States.
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States.|Department of Pathology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Matthew
authors.identifier: http://orcid.org/0000-0003-3753-4412
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006019:Glycolysis; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D009243:NAD / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D000069292:Pyroptosis; D012486:Salmonella typhimurium / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009243:NAD
keywords: Caspase-1; NLRP3; Salmonella typhimurium; glycolysis; immunology; infectious disease; inflammasome; microbiology; mouse; pyroptosis