Activation of osmo-sensitive LRRC8 anion channels in macrophages is important for micro-crystallin joint inflammation

Twinu Wilson Chirayath, Matthias Ollivier, Mete Kayatekin, Isabelle Rubera, Chinh Nghia Pham, Jonas Friard, Nathalie Linck, Hélene Hirbec, Christèle Combes, Mylène Zarka, Frédéric Lioté, Pascal Richette, Francois Rassendren, Vincent Compan (), Christophe Duranton () and Hang Korng Ea ()
Additional contact information
Twinu Wilson Chirayath: AP-HP
Matthias Ollivier: INSERM
Mete Kayatekin: Science & Therapeutics
Isabelle Rubera: Science & Therapeutics
Chinh Nghia Pham: AP-HP
Jonas Friard: Science & Therapeutics
Nathalie Linck: INSERM
Hélene Hirbec: INSERM
Christèle Combes: INPT-CNRS
Mylène Zarka: AP-HP
Frédéric Lioté: AP-HP
Pascal Richette: AP-HP
Francois Rassendren: INSERM
Vincent Compan: INSERM
Christophe Duranton: Science & Therapeutics
Hang Korng Ea: AP-HP

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Deposition of monosodium urate and calcium pyrophosphate (MSU and CPP) micro-crystals is responsible for painful and recurrent inflammation flares in gout and chondrocalcinosis. In these pathologies, the inflammatory reactions are due to the activation of macrophages responsible for releasing various cytokines including IL-1β. The maturation of IL-1β is mediated by the multiprotein NLRP3 inflammasome. Here, we find that activation of the NLRP3 inflammasome by crystals and concomitant production of IL-1β depend on cell volume regulation via activation of the osmo-sensitive LRRC8 anion channels. Both pharmacological inhibition and genetic silencing of LRRC8 abolish NLRP3 inflammasome activation by crystals in vitro and in mouse models of crystal-induced inflammation. Activation of LRRC8 upon MSU/CPP crystal exposure induces ATP release, P2Y receptor activation and intracellular calcium increase necessary for NLRP3 inflammasome activation and IL-1β maturation. We identify a function of the LRRC8 osmo-sensitive anion channels with pathophysiological relevance in the context of joint crystal-induced inflammation.

Date: 2024
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DOI: 10.1038/s41467-024-52543-8

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