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.
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.
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece; First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
Panagiotis
P
Skendros
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Akrivi
A
Chrysanthopoulou
Université Pierre et Marie Curie, UF d'Histocompatibilité et Immunogénétique, Département d'Immunologie, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, Paris, France.
François
F
Rousset
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Konstantinos
K
Kambas
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Athanasios
A
Arampatzioglou
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Alexandros
A
Mitsios
Université Pierre et Marie Curie, UF d'Histocompatibilité et Immunogénétique, Département d'Immunologie, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, Paris, France.
Veronique
V
Bocly
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Theocharis
T
Konstantinidis
Université Pierre et Marie Curie, UF d'Histocompatibilité et Immunogénétique, Département d'Immunologie, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, Paris, France.
Philippe
P
Pellet
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Iliana
I
Angelidou
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece; First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
Eirini
E
Apostolidou
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Dimitrios
D
Ritis
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Victoria
V
Tsironidou
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
Sotiris
S
Galtsidis
First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
Charalampos
C
Papagoras
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.
Dimitrios
D
Stakos
First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
Georgios
G
Kouklakis
First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
Vasiliki
V
Dalla
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
Maria
M
Koffa
Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany.
Ioannis
I
Mitroulis
Université Pierre et Marie Curie, UF d'Histocompatibilité et Immunogénétique, Département d'Immunologie, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, Paris, France.
Ioannis
I
Theodorou
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.
Konstantinos
K
Ritis
D000328:Adult; D001343:Autophagy; D018450:Disease Progression; D065206:Extracellular Traps / Q000378:metabolism; D010505:Familial Mediterranean Fever / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000276:immunology*; D000071198:Pyrin / Q000235:genetics; D012075:Remission, Spontaneous; D013312:Stress, Physiological / Q000276:immunology; D013315:Stress, Psychological / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*; D055815:Young Adult
C469991:DDIT4 protein, human; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D000071198:Pyrin; D014157:Transcription Factors
IL-1β; Regulated in development and DNA damage responses 1; autophagy; familiar Mediterranean fever; inflammation; neutrophil extracellular traps; stress