Browsing by Subject "Autoinflammatory disease"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Publication
    Open Access
    4-octyl itaconate reduces NLRP3 inflammasome constitutive activation with cryopyrin-associated periodic syndrome p.R262W, p.D305N and p.T350M variants
    (Springer, Birkhäuser Verlag, 2025-05-23) Molina-López, Cristina; Hurtado-Navarro, Laura; O'Neill, Luke A.J.; Pelegrin, Pablo; Bioquímica y Biología Molecular B e Inmunología
    Cryopyrin-associated periodic syndrome (CAPS) is a condition characterized by dominant genetic variants in the NLRP3 gene, leading to the formation of constitutively active inflammasomes. These inflammasomes play a crucial role in the inflammatory episodes experienced by CAPS patients, primarily driven by the production of interleukin (IL)-1. Although treatment with IL-1 blockers is effective for CAPS, some patients develop refractory responses and adverse reactions to these therapies. Consequently, there is a need for novel treatments for CAPS patients. Promising candidates are the derivatives of itaconate, which have been shown to impair NLRP3 inflammasome activation and IL-1 release in blood mononuclear cells from CAPS patients. In this study, we provide insight into the inhibitory mechanisms of the itaconate derivative 4-octyl itaconate (4-OI) on NLRP3 with different (p.R262W, p.D305N and p.T350M) gain-of-function mutations associated with CAPS. Notably, 4-OI effectively blocks the basal auto-activation of the inflammasome formed by NLRP3 p.R262W, p.D305N and p.T350M variants, resulting in reduced caspase-1 activation, gasdermin D processing, and IL-18 release. Furthermore, after lipopolysaccharide priming of macrophages, 4-OI also decreases IL-1 gene expression and release. Overall, 4-OI impairs CAPS p.D305N-associated inflammasome function at multiple levels, and therapeutic agents based on itaconate could be a promising therapeutic approach to managing inflammatory episodes in CAPS patients carrying p.R262W, p.D305N or p.T350M variants.
  • Thumbnail Image
    Publication
    Open Access
    Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
    (Nature Research, 2024-02-06) Molina-López, Cristina; Hurtado-Navarro, Laura; Garcia, Carlos J.; Angosto-Bazarra, Diego; Vallejo, Fernando; Tapia-Abellán, Ana; Marques-Soares, Joana R.; Vargas, Carmen; Bujan-Rivas, Segundo; Tomás-Barberán, Francisco A.; Arostegui, Juan I.; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
    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.