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Ectosomes of polymorphonuclear neutrophils activate multiple signaling pathways in macrophages

Eken, Ceylan and Sadallah, Salima and Martin, Perrine J. and Treves, Susan and Schifferli, Jurg A.. (2013) Ectosomes of polymorphonuclear neutrophils activate multiple signaling pathways in macrophages. Immunobiology, 218 (3). pp. 382-392.

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Abstract

Ectosomes are vesicles shed directly from the cell surface. Human polymorphonuclear neutrophils release ectosomes (PMN-Ect) upon their activation. PMN-Ect expose phosphatidylserine (PS) on the outer leaflet of the plasma membrane, and down-modulate the inflammatory response of human macrophages and dendritic cells exposed to TLR-2 and -4 ligands. This down-modulation is mediated by PS via the engagement and activation of the Mer receptor tyrosine kinase (MerTK). In the present study, we demonstrate that exposure of macrophages to PMN-Ect activates directly 2 additional pathways, an immediate Ca(2+) flux and a rapid release of TGF-beta1. As expected, the Ca(2+) flux was necessary for the activation of TLR-2 pathway with the release of cytokines. However, MerTK blockade with antibodies did not modify the Ca(2+) flux, indicating an independent activation of Ca(2+) by PMN-Ect. Striking was that the rapid release of TGF-beta1 was independent of the MerTK pathway and did not require a Ca(2+) flux. TGF-beta1 was present in cytosolic storage pools, which were depleted after exposure of the macrophages to PMN-Ect, and no increase in TGF-beta1 mRNA could be detected in the 3 first hours when maximal release had occurred. The release of TGF-beta1 by macrophages was seen only for PMN-Ect and not for PS-liposomes or erythrocyte ectosomes, which express PS. However, blocking the PS of PMN-Ect inhibited TGF-beta1 release, suggesting that PS expression was necessary although not sufficient for this release. Interestingly, the effects of PMN-Ect pre-exposure were lasting for 24h with the macrophages being less receptive to TLR-2 activation and TGF-beta1 stores remaining low. In sum, PMN-Ect induce several signaling pathways in resting and stimulated macrophages, which include independently the MerTK pathway, Ca(2+) flux and the release of stored TGF-beta1, and each might influence the immunomodulatory effects of macrophages.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin
03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Immunonephrology (Schifferli)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
UniBasel Contributors:Schifferli, Jürg A. and Treves, Susan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0171-2985
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:11 May 2017 08:33
Deposited On:25 Oct 2013 08:33

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