Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: Correlation with MEFV genotype

Alessia Omenetti, Sonia Carta, Laura Delfino, Alberto Martini, Marco Gattorno, Anna Rubartelli

Research output: Contribution to journalArticle

Abstract

Objectives: To define in patients affected by familial Mediterranean fever (FMF) whether or not interleukin (IL)-1β secretion (1) is enhanced, (2) correlates with the type of MEFV mutation and (3) is mediated by NLRP3. Methods: Freshly isolated monocytes from 21 patients with FMF (12 homozygous and 9 heterozygous), 14 MEFV healthy carriers and 30 healthy donors (HDs), unstimulated or after lipopolysaccharide (LPS)-induced activation, were analysed for redox state (production of reactive oxygen species (ROS) and antioxidant responses) and IL-1β and IL-1 receptor antagonist (IL-1Ra) secretion. NLRP3 down-modulation was induced by in vitro silencing of the NLRP3 gene. Results: LPS-stimulated monocytes from patients with FMF displayed enhanced IL-1β secretion, which correlated with number and penetrance of MEFV mutations. Silencing of NLRP3 consistently inhibited IL-1β secretion. As in other autoinflammatory diseases, FMF monocytes produced more ROS than genetically negative cells from HDs. Unlike in cryopyrin-associated periodic fever syndromes (CAPS), however, they were characterised by a conserved and sustained antioxidant response. Consistent with this finding, activated MEFV-mutated monocytes did not exhibit the functional indicators of oxidative stress observed in CAPS, including accelerated IL-1β secretion and deficient production of IL-1Ra. Conclusions: MEFV-mutated monocytes display enhanced IL-1β secretion, which correlates with number of high-penetrance mutations and level of endogenous ROS. Unlike NLRP3-mutated cells, monocytes carrying MEFV mutations withstand oxidative stress and preserve IL-1Ra production, thereby limiting inflammation. Finally, in contrast with that found in the animal model, the increased secretion of IL-1β by LPS-stimulated FMF monocytes is NLRP3-dependent.

Original languageEnglish
Pages (from-to)462-469
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume73
Issue number2
DOIs
Publication statusPublished - Feb 2014

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

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