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Monosodium Urate Crystals Generate Nuclease-Resistant Neutrophil Extracellular Traps via a Distinct Molecular Pathway

The Journal of immunology (1950), 2018-03, Vol.200 (5), p.1802-1816 [Peer Reviewed Journal]

Copyright © 2018 by The American Association of Immunologists, Inc. ;Copyright American Association of Immunologists Mar 1, 2018 ;ISSN: 0022-1767 ;EISSN: 1550-6606 ;DOI: 10.4049/jimmunol.1701382 ;PMID: 29367211

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Title:
Monosodium Urate Crystals Generate Nuclease-Resistant Neutrophil Extracellular Traps via a Distinct Molecular Pathway
Author: Chatfield, Simon M ; Grebe, Kathrin ; Whitehead, Lachlan W ; Rogers, Kelly L ; Nebl, Thomas ; Murphy, James M ; Wicks, Ian P
Subjects: Actin ; Apoptosis ; Autopsy ; Cell death ; Chromatin ; Crystals ; Deoxyribonuclease ; Deoxyribonucleic acid ; DNA ; Elastase ; Extracellular Traps - metabolism ; Gout ; Gout - metabolism ; Humans ; Hyphae ; Inflammation ; Leukocyte Elastase - metabolism ; Lysosomes ; Male ; Mortality ; NAD(P)H oxidase ; Neutrophils ; Neutrophils - metabolism ; Nuclease ; Synovial Fluid - metabolism ; Tissues ; Uric acid ; Uric Acid - metabolism
Is Part Of: The Journal of immunology (1950), 2018-03, Vol.200 (5), p.1802-1816
Description: Neutrophil extracellular traps (NETs) and the cell death associated with it (NETosis) have been implicated in numerous diseases. Mechanistic studies of NETosis have typically relied on nonphysiological stimuli, such as PMA. The human disease of gout is caused by monosodium urate (MSU) crystals. We observed that DNA consistent with NETs is present in fluid from acutely inflamed joints of gout patients. NETs also coat the crystals found in uninflamed tophi of chronic gout patients. We developed a quantitative, live cell imaging assay, which measures the key features of NETosis, namely, cell death and chromatin decondensation. We show that MSU and other physiologically relevant crystals induce NETosis through a molecular pathway that is distinct from PMA and hyphae. Crystals interact with lysosomes to induce NADPH oxidase-independent cell death, with postmortem chromatin decondensation mediated by neutrophil elastase. The resulting MSU-induced NETs are enriched for actin and are resistant to serum and DNase degradation. These findings demonstrate a distinct physiological NETosis pathway in response to MSU crystals, which coats MSU crystals in DNA that persists in tissues as gouty tophi.
Publisher: United States: American Association of Immunologists
Language: English
Identifier: ISSN: 0022-1767
EISSN: 1550-6606
DOI: 10.4049/jimmunol.1701382
PMID: 29367211
Source: GFMER Free Medical Journals
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Monosodium Urate Crystals Generate Nuclease-Resistant Neutrophil Extracellular Traps via a Distinct Molecular Pathway

Copyright © 2018 by The American Association of Immunologists, Inc. ;Copyright American Association of Immunologists Mar 1, 2018 ;ISSN: 0022-1767 ;EISSN: 1550-6606 ;DOI: 10.4049/jimmunol.1701382 ;PMID: 29367211

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