Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis

Girbl, T. et al. (2018) Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis. Immunity, 49(6), 1062-1076.e6. (doi: 10.1016/j.immuni.2018.09.018) (PMID:30446388) (PMCID:PMC6303217)

174497.pdf - Published Version
Available under License Creative Commons Attribution.



Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine "depot" in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources. [Abstract copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.]

Item Type:Articles
Additional Information:This work was supported by funds from the British Heart Foundation (FS/14/3/30518 to T.G. and S.N.), the People Programme (Marie Curie Actions) of the EU’s 7th Framework Programme (FP7/2007-2013) under REA grant agreement 608765 (to T.G. and S.N.), and by the Wellcome Trust (098291/Z/12/Z to S.N.). D.S. is supported by the CNIC, SAF2016-79040-R from the Spanish Ministerio de Ciencia, and ERC-2016-CoG 725091 from the European Research Council. M.T. and A.R. are supported by the Sinergia grant CRSII3_160719 of the Swiss National Science Foundation. G.G. is supported by the Wellcome Trust and the MRC. U.H.v.A. and A.T. are supported by the Ragon Institute of MGH, MIT and Harvard and the HMS Center for Immune Imaging.
Keywords:ACKR1, CXCR2, chemokines, endothelium, extravasation, inflammation, neutrophils, pericytes.
Glasgow Author(s) Enlighten ID:Graham, Professor Gerard
Authors: Girbl, T., Lenn, T., Perez, L., Rolas, L., Barkaway, A., Thiriot, A., Del Fresno, C., Lynam, E., Hub, E., Thelen, M., Graham, G., Alon, R., Sancho, D., von Andrian, U. H., Voisin, M.-B., Rot, A., and Nourshargh, S.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Immunity
ISSN (Online):1097-4180
Published Online:13 November 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Immunity 49(6):1062-1076.e6
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record