title: Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals.
abstract: Hyperuricemia is strongly linked to cardiovascular complications including atherosclerosis and thrombosis. In individuals with hyperuricemia, needle-shaped monosodium urate crystals (nsMSU) frequently form within joints or urine, giving rise to gouty arthritis or renal calculi, respectively. These nsMSU are potent instigators of neutrophil extracellular trap (NET) formation. Little is known on the mechanism(s) that prevent nsMSU formation within hyperuricemic blood, which would potentially cause detrimental consequences for the host. Here, we report that complement proteins and fetuins facilitate the continuous clearance by blood-borne phagocytes and resident macrophages of small urate microaggregates (UMA; <1 μm in size) that initially form in hyperuricemic blood. If this clearance fails, UMA exhibit bipolar growth to form typical full-sized nsMSU with a size up to 100 μm. In contrast to UMA, nsMSU stimulated neutrophils to release NETs. Under conditions of flow, nsMSU and NETs formed densely packed DNase I-resistant tophus-like structures with a high obstructive potential, highlighting the importance of an adequate and rapid removal of UMA from the circulation. Under pathological conditions, intravascularly formed nsMSU may hold the key to the incompletely understood association between NET-driven cardiovascular disease and hyperuricemia.
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Pieterse
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.|Institute of Rheumatology, Resavska 69, Belgrade, Serbia.
authors.forename: Ivica
authors.initials: I
authors.lastname: Jeremic
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Czegley
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weidner
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Mona H C
authors.initials: MH
authors.lastname: Biermann
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Veissi
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Maueröder
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Schauer
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.|Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
authors.forename: Rostyslav
authors.initials: R
authors.lastname: Bilyy
authors.affiliation: Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.
authors.forename: Tetiana
authors.initials: T
authors.lastname: Dumych
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Munoz
authors.affiliation: Department of Rheumatology, University Hospital of Lund, Lund, Sweden.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
authors.affiliation: Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D065206:Extracellular Traps / Q000378:metabolism*; D006801:Humans; D033461:Hyperuricemia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D014527:Uric Acid