2. Academic Validation
  3. Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production

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

  • Nat Commun. 2024 Feb 6;15(1):1096. doi: 10.1038/s41467-024-44990-0.
Cristina Molina-López 1,  Laura Hurtado-Navarro 1,  Carlos J García 2,  Diego Angosto-Bazarra 1,  Fernando Vallejo 2,  Ana Tapia-Abellán 1 3,  Joana R Marques-Soares 4,  Carmen Vargas 5,  Segundo Bujan-Rivas 4,  Francisco A Tomás-Barberán 2,  Juan I Arostegui 6 7 8,  Pablo Pelegrin 9 10
Affiliations

Affiliations

  • 1 Molecular Inflammation Group, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla-IMIB, Murcia, Spain.
  • 2 Quality, Safety and Bioactivity of Plant-Derived Foods, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas (CEBAS-CSIC), Murcia, Spain.
  • 3 Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany.
  • 4 Department of Internal Medicine, Hospital Vall Hebron, Barcelona, Spain.
  • 5 Department of Rheumatology, Hospital Virgen de la Macarena, Sevilla, Spain.
  • 6 Department of Immunology, Hospital Clínic, Barcelona, Spain.
  • 7 Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
  • 8 School of Medicine, Universitat de Barcelona, Barcelona, Spain.
  • 9 Molecular Inflammation Group, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla-IMIB, Murcia, Spain. pablopel@um.es.
  • 10 Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, 30120, Murcia, Spain. pablopel@um.es.
PMID: 38321014 DOI: 10.1038/s41467-024-44990-0
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.

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