A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors

Arinna Bertoni, Sonia Carta, Chiara Baldovini, Federica Penco, Enrica Balza, Silvia Borghini, Marco Di Duca, Emanuela Ognio, Alessio Signori, Paolo Nozza, Francesca Schena, Patrizia Castellani, Claudia Pastorino, Carola Perrone, Laura Obici, Alberto Martini, Isabella Ceccherini, Marco Gattorno, Anna Rubartelli, Sabrina Chiesa

Research output: Contribution to journalArticlepeer-review


Background: Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) gene, which cause uncontrolled IL-1β secretion. Proton pump inhibitors (PPIs), which are commonly used as inhibitors of gastric acid production, also have anti-inflammatory properties, protect mice from sepsis, and prevent IL-1β secretion by monocytes from patients with CAPS. Objective: We sought to develop a novel Nlrp3 knock-in (KI) mouse model of CAPS to study amyloidosis, a severe CAPS complication, and test novel therapeutic approaches. Methods: We generated KI mice by engineering the N475K mutation, which is associated with the CAPS phenotype, into the mouse Nlrp3 gene. KI and wild-type mice received PPIs or PBS intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development. Results: Mutant Nlrp3 KI mice displayed features that recapitulate the immunologic and clinical phenotype of CAPS. They showed systemic inflammation with high levels of serum proinflammatory cytokines, inflammatory infiltrates in various organs, and amyloid deposits in the spleen, liver, and kidneys. Toll-like receptor stimulated macrophages from KI mice secreted high levels of IL-1β, IL-18, and IL-1α but low amounts of IL-1 receptor antagonist. Treatment of KI mice with PPIs had a clear clinical effect, showing a reduction in inflammatory manifestations, regression of amyloid deposits, and normalization of proinflammatory and anti-inflammatory cytokine production by macrophages. Conclusion: Nlrp3 KI mice displayed a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti–IL-1 drugs in patients with CAPS and other IL-1–driven diseases.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Publication statusPublished - Jan 1 2019


  • Cryopyrin-associated periodic syndromes
  • IL-1β
  • Nlrp3 mice
  • NOD-like receptor family
  • proton pump inhibitor
  • pyrin domain containing 3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


Dive into the research topics of 'A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors'. Together they form a unique fingerprint.

Cite this