TY - JOUR
T1 - Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis
AU - Girbl, Tamara
AU - Lenn, Tchern
AU - Perez, Lorena
AU - Rolas, Loic
AU - Barkaway, Anna
AU - Thiriot, Aude
AU - del Fresno, Carlos
AU - Lynam, Eleanor
AU - Hub, Elin
AU - Thelen, Marcus
AU - Graham, Gerard
AU - Alon, Ronen
AU - Sancho, David
AU - von Andrian, Ulrich H.
AU - Voisin, Mathieu-Benoit
AU - Rot, Antal
AU - Nourshargh, Sussan
PY - 2018/12/18
Y1 - 2018/12/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058358736&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2018.09.018
DO - 10.1016/j.immuni.2018.09.018
M3 - Article
SN - 1074-7613
VL - 49
SP - 1062
EP - 1076
JO - Immunity
JF - Immunity
IS - 6
ER -