title: Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout.
abstract: BACKGROUND
  Gout is a prevalent inflammatory arthritis affecting 1-2% of adults characterized by activation of innate immune cells by monosodium urate (MSU) crystals resulting in the secretion of interleukin-1β (IL-1β). Since neutrophils play a major role in gout we sought to determine whether their activation may involve the formation of proinflammatory neutrophil extracellular traps (NETs) in relation to autophagy and IL-1β.
  
  
  RESULTS
  Synovial fluid neutrophils from six patients with gout crisis and peripheral blood neutrophils from six patients with acute gout and six control subjects were isolated. MSU crystals, as well as synovial fluid or serum obtained from patients with acute gout, were used for the treatment of control neutrophils. NET formation was assessed using immunofluorescence microscopy. MSU crystals or synovial fluid or serum from patients induced NET formation in control neutrophils. Importantly, NET production was observed in neutrophils isolated from synovial fluid or peripheral blood from patients with acute gout. NETs contained the alarmin high mobility group box 1 (HMGB1) supporting their pro-inflammatory potential. Inhibition of phosphatidylinositol 3-kinase signaling or phagolysosomal fusion prevented NET formation, implicating autophagy in this process. NET formation was driven at least in part by IL-1β as demonstrated by experiments involving IL-1β and its inhibitor anakinra.
  
  
  CONCLUSIONS
  These findings document for the first time that activation of neutrophils in gout is associated with the formation of proinflammatory NETs and links this process to both autophagy and IL-1β. Modulation of the autophagic machinery may represent an additional therapeutic study in crystalline arthritides.
authors.affiliation: First Department of Internal Medicine, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mitroulis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kambas
authors.forename: Akrivi
authors.initials: A
authors.lastname: Chrysanthopoulou
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Skendros
authors.forename: Eirini
authors.initials: E
authors.lastname: Apostolidou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kourtzelis
authors.forename: Georgios I
authors.initials: GI
authors.lastname: Drosos
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Boumpas
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Ritis
mesh_terms: D000208:Acute Disease; D001343:Autophagy / Q000187:drug effects; D003460:Crystallization; D004247:DNA / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D006073:Gout / Q000378:metabolism* / Q000473:pathology*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects; D014527:Uric Acid / Q000494:pharmacology
chemical_list: D024243:HMGB1 Protein; D053583:Interleukin-1beta; D014527:Uric Acid; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases