Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production

Cristina Molina-López, Laura Hurtado-Navarro, Carlos García, Diego Angosto-Bazarra, Fernando Vallejo, Ana Tapia-Abellán, Joana R. Marques-Soares, Carmen Vargas, Segundo Bujan-Rivas, Francisco A. Tomás-Barberán, Juan I. Arostegui and Pablo Pelegrin ()
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Cristina Molina-López: Molecular Inflammation Group, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla–IMIB
Laura Hurtado-Navarro: Molecular Inflammation Group, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla–IMIB
Diego Angosto-Bazarra: Molecular Inflammation Group, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla–IMIB
Fernando Vallejo: Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC)
Ana Tapia-Abellán: Molecular Inflammation Group, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla–IMIB
Joana R. Marques-Soares: Hospital Vall Hebron
Carmen Vargas: Hospital Virgen de la Macarena
Segundo Bujan-Rivas: Hospital Vall Hebron
Francisco A. Tomás-Barberán: Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC)
Juan I. Arostegui: Hospital Clínic
Pablo Pelegrin: Molecular Inflammation Group, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla–IMIB

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44990-0

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