Neutrophil microvesicles resolve gout by inhibiting C5a-mediated priming of the inflammasome

Arun Cumpelik, Barbara Ankli, Daniel Zecher, Jürg A. Schifferli

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Objectives Gout is a highly inflammatory but selflimiting joint disease induced by the precipitation of monosodium urate (MSU) crystals. While it is well established that inflammasome activation by MSU mediates acute inflammation, little is known about the mechanism controlling its spontaneous resolution. The aim of this study was to analyse the role of neutrophilderived microvesicles (PMN-Ecto) in the resolution of acute gout. Methods PMN-Ecto were studied in a murine model of MSU-induced peritonitis using C57BL/6, MerTK-/- and C5aR-/- mice. The peritoneal compartment was assessed for the number of infiltrating neutrophils (PMN), neutrophil microvesicles (PMN-Ecto), cytokines(interleukin-1β, TGFβ) and complement factors (C5a). Human PMN-Ecto were isolated from exudates of patients undergoing an acute gouty attack and functionally tested in vitro. Results C5a generated after the injection of MSU primed the inflammasome for IL-1β release. Neutrophils infiltrating the peritoneum in response to C5a released phosphatidylserine (PS)-positive PMN-Ecto early on in the course of inflammation. These PMN-Ecto in turn suppressed C5a priming of the inflammasome and consequently inhibited IL-1β release and neutrophil influx. PMN-Ecto-mediated suppression required surface expression of the PS-receptor MerTK and could be reproduced using PS-expressing liposomes. In addition, ectosomes triggered the release of TGFβ independent of MerTK. TGFβ, however, was not sufficient to control acute MSU-driven inflammation in vivo. Finally, PMNEcto from joint aspirates of patients with gouty arthritis had similar anti-inflammatory properties. Conclusions PMN-Ecto-mediated control of inflammasome-driven inflammation is a compelling concept of autoregulation initiated early on during PMN activation in gout.

Original languageEnglish
Pages (from-to)1236-1245
Number of pages10
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number6
DOIs
StatePublished - Jun 2016
Externally publishedYes

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