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

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


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.

MeSH terms

  • Adult
  • Autophagy
  • Disease Progression
  • Extracellular Traps / metabolism
  • Familial Mediterranean Fever / genetics
  • Familial Mediterranean Fever / immunology*
  • Female
  • Humans
  • Inflammation / immunology*
  • Interleukin-1beta / metabolism
  • Male
  • Neutrophils / immunology*
  • Pyrin / genetics
  • Remission, Spontaneous
  • Stress, Physiological / immunology
  • Stress, Psychological / immunology*
  • Transcription Factors / metabolism*
  • Young Adult


  • DDIT4 protein, human
  • Interleukin-1beta
  • MEFV protein, human
  • Pyrin
  • Transcription Factors