Cumpelik, Arun and Ankli, Barbara and Zecher, Daniel and Schifferli, Jurg A. (2016) Neutrophil microvesicles resolve gout by inhibiting C5a-mediated priming of the inflammasome. ANNALS OF THE RHEUMATIC DISEASES, 75 (6). pp. 1236-1245. ISSN 0003-4967, 1468-2060
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Objectives Gout is a highly inflammatory but self-limiting 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 neutrophil-derived 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-1 beta, TGF beta) 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-1 beta 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-1 beta 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 TGF beta independent of MerTK. TGF beta, however, was not sufficient to control acute MSU-driven inflammation in vivo. Finally, PMN-Ecto 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KAPPA-B ACTIVATION; PERIPHERAL-BLOOD MONOCYTES; MONOSODIUM URATE CRYSTALS; GROWTH-FACTOR BETA-1; POLYMORPHONUCLEAR NEUTROPHILS; APOPTOTIC CELLS; DENDRITIC CELLS; CUTTING EDGE; RESOLUTION; RECEPTORS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Mar 2019 13:44 |
| Last Modified: | 25 Mar 2019 13:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2886 |
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