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

• Published in: Journal of allergy and clinical immunology Vol. 140; no. 5; pp. 1378 - 1387.e13
• Main Authors: Skendros, Panagiotis, Chrysanthopoulou, Akrivi, Rousset, François, Kambas, Konstantinos, Arampatzioglou, Athanasios, Mitsios, Alexandros, Bocly, Veronique, Konstantinidis, Theocharis, Pellet, Philippe, Angelidou, Iliana, Apostolidou, Eirini, Ritis, Dimitrios, Tsironidou, Victoria, Galtsidis, Sotiris, Papagoras, Charalampos, Stakos, Dimitrios, Kouklakis, Georgios, Dalla, Vasiliki, Koffa, Maria, Mitroulis, Ioannis, Theodorou, Ioannis, Ritis, Konstantinos
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2017; Elsevier Limited
• Subjects: Adult; Age; Allergy and Immunology; Arthritis; Autophagy; Bacterial infections; Cell activation; Deoxyribonucleic acid; Disease; Disease Progression; DNA; DNA damage; Enzyme-linked immunosorbent assay; Epinephrine; Extracellular Traps - metabolism; Familial Mediterranean fever; Familial Mediterranean Fever - genetics; Familial Mediterranean Fever - immunology; familiar Mediterranean fever; Female; Fever; Flow cytometry; Gene expression; Humans; IL-1β; Immunoblotting; Immunofluorescence; Infections; Inflammation; Inflammation - immunology; Interleukin-1beta - metabolism; Juvenile rheumatoid arthritis; Leucine; Leukocytes (neutrophilic); Male; neutrophil extracellular traps; Neutrophils; Neutrophils - immunology; Peroxidase; Phagocytosis; Proteins; Pyrin - genetics; Pyrin protein; Regulated in development and DNA damage responses 1; Remission; Remission, Spontaneous; Ribonucleic acid; RNA; Rodents; stress; Stress, Physiological - immunology; Stress, Psychological - immunology; Transcription Factors - metabolism; Values; Young Adult; stress; AOSD; autophagy; neutrophil extracellular traps; IL-1β; MEFV; MPO; Regulated in development and DNA damage responses 1; inflammation; NALP3; familiar Mediterranean fever; DDIT4; CitH3; NLRP3; NET; REDD1; SQSTM1; FMF; Mediterranean fever; DNA damage–inducible transcript 4; Myeloperoxidase; Familial Mediterranean fever; NACHT, LRR, and PYD domain-containing protein 3; Citrullinated-histone H3; Sequestosome 1; Neutrophil extracellular trap; Adult-onset Still's disease; Nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing 3
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.02.021

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. 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. 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. 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. 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. [Display omitted]