Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Issue 2 (16th March 2013)

• Record Type: Journal Article
• Authors: Omenetti, Alessia; Carta, Sonia; Delfino, Laura; Martini, Alberto; Gattorno, Marco; Rubartelli, Anna
• Is Part Of: Annals of the rheumatic diseases. Volume 73:Issue 2(2014)
• Page Start: 462
• Page End: 469
• Publication Date: 2013-03-16
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2012-202774
• Languages: English
• ISSNs: 0003-4967

Abstract

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.