Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Feb 2024
06 Feb 2024
Historique:
received:
02
05
2023
accepted:
11
01
2024
medline:
7
2
2024
pubmed:
7
2
2024
entrez:
6
2
2024
Statut:
epublish
Résumé
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1β production. Although these are gain-of-function variants characterized by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4 A. The constitutively active NLRP3-inflammasome of CAPS is responsive to the selective NLRP3 inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-κB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1β production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1β-dependent inflammatory episodes through immunometabolism modulation.
Identifiants
pubmed: 38321014
doi: 10.1038/s41467-024-44990-0
pii: 10.1038/s41467-024-44990-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1096Subventions
Organisme : Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)
ID : PID2020-116709RB-I00
Organisme : Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)
ID : RED2022-134511-T
Organisme : Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)
ID : BG20/00060
Organisme : Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)
ID : CNS2022-135101
Organisme : Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)
ID : SAF2017-88276-R
Organisme : Fundación Séneca (Fundacion Seneca)
ID : 20859/PI/18
Organisme : Fundación Séneca (Fundacion Seneca)
ID : 21897/PI/22
Organisme : Fundación Séneca (Fundacion Seneca)
ID : 21214/FPI/19
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : AC22/00009
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : DTS21/00080
Informations de copyright
© 2024. The Author(s).
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