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

作者：Tamara Girbl, Tchern Lenn, Lorena Pérez, Loïc Rolas, Anna Barkaway, Aude Thiriot, Carlos del Fresno, Eleanor G. Lynam, Elin Hub, Marcus Thelen, Gerard J. Graham, Ronen Alon, David Sancho, Ulrich H. von Andrian, Mathieu-Benoı̂t Voisin, Antal Rot, Sussan Nourshargh · 发表于：Immunity · 年份：2018 · DOI：10.1016/j.immuni.2018.09.018 · 被引用次数：381 · 研究领域：Chemokine receptors and signaling、Immune Response and Inflammation、Cell Adhesion Molecules Research

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.