REDD1 links stress with IL-1β-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps

Publication date: Available online 23 March 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Panagiotis Skendros, Akrivi Chrysanthopoulou, François Rousset, Konstantinos Kambas, Athanasios Arampatzioglou, Alexandros Mitsios, Veronique Bocly, Theocharis Konstantinidis, Philippe Pellet, Iliana Angelidou, Eirini Apostolidou, Dimitrios Ritis, Victoria Tsironidou, Sotiris Galtsidis, Charalampos Papagoras, Dimitrios Stakos, Georgios Kouklakis, Vasiliki Dalla, Maria Koffa, Ioannis Mitroulis, Ioannis Theodorou, Konstantinos Ritis
BackgroundFamilial Mediterranean fever (FMF) is an IL-1β-dependent autoinflammatory disease caused by mutations of MEFV encoding pyrin, and characterised by inflammatory attacks, induced by physical or psychological stress.ObjectiveWe investigate the underlying mechanism that links stress-induced inflammatory attacks with neutrophil activation and release of IL-1β-bearing neutrophil extracellular traps (NETs) in FMF.MethodsRNA-seq was performed in peripheral neutrophils from 3 FMF patients, isolated both during attack and remission, 8 patients in remission and 8 healthy individuals. NET formation and proteins were analysed by confocal immunofluorescence microscopy, immunobloting, MPO-DNA complex ELISA and flow cytometry. Samples from patients suffering from Still's disease and bacterial infections were also used.ResultsStress-related protein REDD1 is significantly over-expressed during FMF attacks. Neutrophils from FMF patients during remission are resistant to autophagy-mediated NET release, which can be overcome via REDD1 induction. Stress-related mediators (e.g. epinephrine) lower this threshold leading to autophagy-driven NET release, while the synchronous inflammatory environment of FMF attack leads to intracellular production of IL-1β and its release through NETs. REDD1 in autolysosomes co-localizes with pyrin and NALP3. Mutated pyrin prohibits this co-localization, leading to higher IL-1β levels on NETs.ConclusionsThis study provides a link between stress and initiation of inflammatory attacks in FMF. REDD1 emerges as an upstream to pyrin regulator of neutrophil function, is involved in NET release, regulation of IL-1β and, may constitute an important piece in the IL-1β-mediated inflammation puzzle.

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Teaser

Stress-induced protein REDD1 is identified as a novel mediator in the pathogenesis of IL-1β-driven inflammation, through regulation of autophagy-mediated release of NETs. This study links environmental stress with inflammation in FMF attack as well as, with other IL-1β-associated autoinflammatory disorders.


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