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Immunity. 2018 Dec 18;49(6):1062-1076.e6. doi: 10.1016/j.immuni.2018.09.018. Epub 2018 Nov 13.

Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis.

Author information

1
Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
2
Department of Microbiology and Immunobiology and HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA.
3
Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
4
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona 6500, Switzerland.
5
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
6
Department of Immunology, The Weizmann Institute of Science, Rehovot 7610001, Israel.
7
Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Centre for Inflammation and Therapeutic Innovation, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Institute for Cardiovascular Prevention, Ludwig-Maximilians University, Munich 80336, Germany.
8
Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Centre for Inflammation and Therapeutic Innovation, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: s.nourshargh@qmul.ac.uk.

Abstract

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.

KEYWORDS:

ACKR1; CXCR2; chemokines; endothelium; extravasation; inflammation; neutrophils; pericytes

PMID:
30446388
PMCID:
PMC6303217
DOI:
10.1016/j.immuni.2018.09.018
[Indexed for MEDLINE]
Free PMC Article

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