Activation of osmo-sensitive LRRC8 anion channels in macrophages is important for micro-crystallin joint inflammation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 Sep 2024
18 Sep 2024
Historique:
received:
04
11
2023
accepted:
12
09
2024
medline:
19
9
2024
pubmed:
19
9
2024
entrez:
18
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39294178
doi: 10.1038/s41467-024-52543-8
pii: 10.1038/s41467-024-52543-8
doi:
Substances chimiques
NLR Family, Pyrin Domain-Containing 3 Protein
0
Inflammasomes
0
Interleukin-1beta
0
LRRC8A protein, mouse
0
Membrane Proteins
0
Uric Acid
268B43MJ25
LRRC8A protein, human
0
Nlrp3 protein, mouse
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8179Subventions
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-22-CE14-0020
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-22-CE14-0020
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-22-CE14-0020
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-22-CE14-0020
Informations de copyright
© 2024. The Author(s).
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