Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death

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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 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.

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Laura E Sanman

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Yu Qian

Department of Chemistry, Boston College, Chestnut Hill, United States

Competing interests
The authors declare that no competing interests exist.
Nicholas A Eisele

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Tessie M Ng

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Wouter A van der Linden

Department of Pathology, Stanford University School of Medicine, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Denise M Monack

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Eranthie Weerapana

Department of Chemistry, Boston College, Chestnut Hill, United States

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The authors declare that no competing interests exist.
Matthew Bogyo

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States

For correspondence
mbogyo@stanford.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This work was approved under ABP protocol 1331 (Entitled Chemical probes to study host responses to bacterial pathogens) and APLAC protocol 18026. Primary cells were isolated from mouse bone marrow following strict accordance with the NIH guide for the care and use of laboratory animals. These protocols were reviewed and approved by the Environmental Health and Safety Department of Stanford University and the Institutional Animal Care and Use Committee of Stanford University, respectively.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.