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Neutrophil extracellular traps regulate IL-1β-mediated inflammation in familial Mediterranean fever
  1. Eirini Apostolidou1,2,
  2. Panagiotis Skendros1,2,
  3. Konstantinos Kambas1,
  4. Ioannis Mitroulis3,
  5. Theocharis Konstantinidis1,
  6. Akrivi Chrysanthopoulou1,
  7. Konstantinos Nakos4,
  8. Victoria Tsironidou1,
  9. Maria Koffa4,
  10. Dimitrios T Boumpas5,6,
  11. Konstantinos Ritis1,2
  1. 1Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece
  2. 2First Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis, Greece
  3. 3Department of Clinical Pathobiochemistry, Technical University Dresden, Dresden, Germany
  4. 4Laboratory of Cellular and Molecular Biology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
  5. 5Fourth Department of Internal Medicine, National University of Athens Medical School, Athens, Greece
  6. 6Biomedical Research Foundation of Academy of Athens, Centre of Immunology and Transplantations, Athens, Greece
  1. Correspondence to Professor Konstantinos Ritis, PhD, University Hospital of Alexandroupolis, Dragana, Alexandroupolis 68100, Greece; ritis2{at}otenet.gr

Abstract

Objective Inflammatory attacks of familial Mediterranean fever (FMF) are characterised by circulation and influx of high number of polymorphonuclear neutrophils (PMN) in the affected sites and profound therapeutic effect of IL-1β inhibitors. We investigated the role of neutrophil extracellular traps (NET) in the pathogenesis of FMF, and their involvement in IL-1β production.

Methods Blood samples were obtained from six FMF patients during remissions and from three patients during attacks. NET formation and NET components were studied by fluorescence techniques, immunobloting and MPO-DNA complex ELISA.

Results PMNs from patients released NETs decorated with IL-1β during disease attacks. On the other hand, PMNs from patients during remission were resistant to inflammatory stimuli that induce NET release in PMNs from control subjects. Lower basal autophagy levels were identified in PMNs during remission, while induction of autophagy facilitated NET release, suggesting that autophagy is involved in the regulation of NET release. During the resolution of attacks, inhibition of NET formation by negative feedback mechanism was also observed. The anti-inflammatory agents, colchicine and DNAse I, inhibited IL-1β production in PMNs and IL-1β activity in NETs, respectively.

Conclusions We suggest two additive events for triggering the FMF attack; the production of IL-1β by PMNs and its release through NETs. At the same time NETs, homeostatically, downregulate further NETosis, facilitating the resolution of attack. Compensatorly, lower basal autophagy of PMNs may protect from crises by attenuating the release of pro-inflammatory NETs.

  • Familial Mediterranean Fever
  • Inflammation
  • Cytokines

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