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J Allergy Clin Immunol. 2017 Nov;140(5):1378-1387.e13. doi: 10.1016/j.jaci.2017.02.021. Epub 2017 Mar 23.

Regulated in development and DNA damage responses 1 (REDD1) links stress with IL-1β-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps.

Author information

1
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece; First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
2
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
3
Université Pierre et Marie Curie, UF d'Histocompatibilité et Immunogénétique, Département d'Immunologie, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, Paris, France.
4
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
5
First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
6
Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany.
7
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece; First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece. Electronic address: kritis@med.duth.gr.

Abstract

BACKGROUND:

Familial Mediterranean fever (FMF) is an IL-1β-dependent autoinflammatory disease caused by mutations of Mediterranean fever (MEFV) encoding pyrin and characterized by inflammatory attacks induced by physical or psychological stress.

OBJECTIVE:

We investigated the underlying mechanism that links stress-induced inflammatory attacks with neutrophil activation and release of IL-1β-bearing neutrophil extracellular traps (NETs) in patients with FMF.

METHODS:

RNA sequencing was performed in peripheral neutrophils from 3 patients with FMF isolated both during attacks and remission, 8 patients in remission, and 8 healthy subjects. NET formation and proteins were analyzed by using confocal immunofluorescence microscopy, immunoblotting, myeloperoxidase-DNA complex ELISA, and flow cytometry. Samples from patients with Still's disease and bacterial infections were used also.

RESULTS:

The stress-related protein regulated in development and DNA damage responses 1 (REDD1) is significantly overexpressed during FMF attacks. Neutrophils from patients with FMF during remission are resistant to autophagy-mediated NET release, which can be overcome through REDD1 induction. Stress-related mediators (eg, epinephrine) decrease this threshold, leading to autophagy-driven NET release, whereas the synchronous inflammatory environment of FMF attack leads to intracellular production of IL-1β and its release through NETs. REDD1 in autolysosomes colocalizes with pyrin and nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing 3. Mutated pyrin prohibits this colocalization, leading to higher IL-1β levels on NETs.

CONCLUSIONS:

This study provides a link between stress and initiation of inflammatory attacks in patients with FMF. REDD1 emerges as a regulator of neutrophil function upstream to pyrin, is involved in NET release and regulation of IL-1β, and might constitute an important piece in the IL-1β-mediated inflammation puzzle.

KEYWORDS:

IL-1β; Regulated in development and DNA damage responses 1; autophagy; familiar Mediterranean fever; inflammation; neutrophil extracellular traps; stress

PMID:
28342915
DOI:
10.1016/j.jaci.2017.02.021
[Indexed for MEDLINE]

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