Monosodium urate crystals generate nuclease-resistant neutrophil extracellular traps via a distinct molecular pathway

Simon M. Chatfield, Kathrin Grebe, Lachlan W. Whitehead, Kelly L. Rogers, Thomas Nebl, James M. Murphy, Ian P. Wicks

Research output: Contribution to journalArticleResearchpeer-review

74 Citations (Scopus)

Abstract

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 DNAconsistent 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 Candida 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.

Original languageEnglish
Pages (from-to)1802-1816
Number of pages15
JournalJournal of Immunology
Volume200
Issue number5
DOIs
Publication statusPublished - 1 Mar 2018
Externally publishedYes

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