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Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9371-E9380. doi: 10.1073/pnas.1812744115. Epub 2018 Sep 19.

Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming.

Author information

1
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M13 9PT Manchester, United Kingdom.
2
Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia, 30120 Murcia, Spain.
3
Manchester Collaborative Centre of Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Core Technology Facility, University of Manchester, M13 9NT Manchester, United Kingdom.
4
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M13 9PT Manchester, United Kingdom; david.brough@manchester.ac.uk.

Abstract

The NLRP3 inflammasome is an important regulator of inflammation and immunity. It is a multimolecular platform formed within cells that facilitates the activation of proinflammatory caspases to drive secretion of cytokines such as interleukin-1β (IL-1β). Knowledge of the mechanisms regulating formation of the NLRP3 inflammasome is incomplete. Here we report Cl- channel-dependent formation of dynamic ASC oligomers and inflammasome specks that remain inactive in the absence of K+ efflux. Formed after Cl- efflux exclusively, ASC specks are NLRP3 dependent, reversible, and inactive, although they further prime inflammatory responses, accelerating and enhancing release of IL-1β in response to a K+ efflux-inducing stimulus. NEK7 is a specific K+ sensor and does not associate with NLRP3 under conditions stimulating exclusively Cl- efflux, but does after K+ efflux, activating the complex driving inflammation. Our investigation delivers mechanistic understanding into inflammasome activation and the regulation of inflammatory responses.

KEYWORDS:

caspase-1; chloride; inflammasome; inflammation; interleukin-1

PMID:
30232264
PMCID:
PMC6176575
[Available on 2019-04-02]
DOI:
10.1073/pnas.1812744115
[Indexed for MEDLINE]

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