title: Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation.
abstract: Neutrophil extracellular traps (NETs) are composed of extracellular DNA fibers with antimicrobial peptides that capture and kill microbes. NETs play a critical role in innate host defense and in autoimmune and inflammatory diseases. While the mechanism of NET formation remains unclear, reactive oxygen species (ROS) produced via activation of NADPH oxidase (Nox) are known to be an important requirement. In this study, we investigated the effect of uric acid (UA) on NET formation. UA, a well-known ROS scavenger, was found to suppress Nox-dependent ROS release in a dose-dependent manner. Low concentrations of UA significantly inhibited Nox-dependent NET formation. However, high concentrations of UA unexpectedly induced, rather than inhibited, NET formation. NETs were directly induced by UA alone in a Nox-independent manner, as revealed by experiments using control neutrophils treated with ROS inhibitors or neutrophils of patients with chronic granulomatous disease who have a congenital defect in ROS production. Furthermore, we found that UA-induced NET formation was partially mediated by NF-κB activation. Our study is the first to demonstrate the novel function of UA in NET formation and may provide insight into the management of patients with hyperuricemia.
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Yasuyuki
authors: Y
authors: Arai
authors: Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors: Yoko
authors: Y
authors: Nishinaka
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Department of Anesthesia, Kyoto City Hospital, Kyoto 604-8845, Japan.
authors: Toshiyuki
authors: T
authors: Arai
authors: Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Makiko
authors: M
authors: Morita
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Kiyomi
authors: K
authors: Mizugishi
authors: Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Souichi
authors: S
authors: Adachi
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Akifumi
authors: A
authors: Takaori-Kondo
authors: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors: Tomohiro
authors: T
authors: Watanabe
authors: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. Electronic address: kouhei@kuhp.kyoto-u.ac.jp.
authors: Kouhei
authors: K
authors: Yamashita
mesh_terms: D000328:Adult; D045604:Extracellular Fluid / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008297:Male; D019255:NADPH Oxidases / Q000276:immunology*; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000276:immunology*; D014527:Uric Acid / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D017382:Reactive Oxygen Species; D014527:Uric Acid; D019255:NADPH Oxidases
keywords: (1)O(2); CGD; Chronic granulomatous disease; DHR; DPI; HBSS; Hanks’ balanced salt solution; MSU; MVP; NADPH oxidase; NET; NF-κB; Neutrophil extracellular trap formation; Nox; PBN; PMA; ROS; Reactive oxygen species; UA; Uric acid; chronic granulomatous disease; dihydrorhodamine 123; diphenyleneiodonium; monosodium urate; neutrophil extracellular trap; phorbol myristate acetate; reactive oxygen species; singlet oxygen; trans-1-(2′-methoxyvinyl)pyrene; uric acid; α-phenyl-N-tert-butyl nitrone