Publication: Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Authors
Molina-López, Cristina ; Hurtado-Navarro, Laura ; Garcia, Carlos J. ; Angosto-Bazarra, Diego ; Vallejo, Fernando ; Marques-Soares, Joana R. ; Vargas, Carmen ; Bujan-Rivas, Segundo ; Tomás-Barberán, Francisco A. ; Arostegui, Juan I. ; Pelegrín Vivancos, Pablo ; Tapia Abellán, Ana
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Publisher
Nature Research
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DOI
https://doi.org/10.1038/s41467-024-44990-0
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info:eu-repo/semantics/article
Description
© 2024, The Author(s). This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted Manuscript version of a Published Work that appeared in final form in Nature Communications. To access the final edited and published work see https://doi.org/10.1038/s41467-024-44990-0
Abstract
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1b production. Although these are gain-of-function variants characterised 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 4A. The constitutively active NLRP3-inflammasome is responsive to the selective NLRP3 inflammasome inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-kB 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-1b 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-1b–dependent inflammatory episodes through immunometabolism modulation.
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Citation
Nature Communications, 2024, Vol. 15 : 1096
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