Neutrophil breaching of the blood vessel pericyte layer during diapedesis requires mast cell-derived IL-17A

Régis Joulia, Idaira María Guerrero-Fonseca, Tamara Girbl, Jonathon A. Coates, Monja Stein, Laura Vázquez-Martínez, Eleanor Lynam, James Whiteford, Michael Schnoor, David Voehringer, Axel Roers, Sussan Nourshargh and Mathieu-Benoit Voisin ()
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Régis Joulia: Queen Mary University of London, Charterhouse Square
Idaira María Guerrero-Fonseca: Queen Mary University of London, Charterhouse Square
Tamara Girbl: Queen Mary University of London, Charterhouse Square
Jonathon A. Coates: Queen Mary University of London, Charterhouse Square
Monja Stein: Queen Mary University of London, Charterhouse Square
Laura Vázquez-Martínez: Queen Mary University of London, Charterhouse Square
Eleanor Lynam: Queen Mary University of London, Charterhouse Square
James Whiteford: Queen Mary University of London, Charterhouse Square
Michael Schnoor: CINVESTAV-IPN
David Voehringer: University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU)
Axel Roers: Heidelberg University Hospital
Sussan Nourshargh: Queen Mary University of London, Charterhouse Square
Mathieu-Benoit Voisin: Queen Mary University of London, Charterhouse Square

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood vessel wall. Here, we show that perivascular mast cells (MC) are key regulators of neutrophil behaviour within the sub-endothelial space of inflamed venules. Using confocal intravital microscopy, we observe directed abluminal neutrophil motility along pericyte processes towards perivascular MCs, a response that created neutrophil extravasation hotspots. Conversely, MC-deficiency and pharmacological or genetic blockade of IL-17A leads to impaired neutrophil sub-endothelial migration and breaching of the pericyte layer. Mechanistically, identifying MCs as a significant cellular source of IL-17A, we establish that MC-derived IL-17A regulates the enrichment of key effector molecules ICAM-1 and CXCL1 in nearby pericytes. Collectively, we identify a novel MC-IL-17A-pericyte axis as modulator of the final steps of neutrophil diapedesis, with potential translational implications for inflammatory disorders driven by increased neutrophil diapedesis.

Date: 2022
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DOI: 10.1038/s41467-022-34695-7

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