Local microvascular leakage promotes trafficking of activated neutrophils to remote organs

Owen-Woods, Charlotte; Joulia, R�gis; Barkaway, Anna; Rolas, Lo�c; Ma, Bin; Nottebaum, Astrid Fee; Arkill, Kenton P.; Stein, Monja; Girbl, Tamara; Golding, Matthew; Bates, David O.; Vestweber, Dietmar; Voisin, Mathieu Benoit; Nourshargh, Sussan

Abstract

Copyright: © 2020, Owen-Woods et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability-enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.

Citation

Owen-Woods, C., Joulia, R., Barkaway, A., Rolas, L., Ma, B., Nottebaum, A. F., …Nourshargh, S. (2020). Local microvascular leakage promotes trafficking of activated neutrophils to remote organs. Journal of Clinical Investigation, 130(5), 2301-2318. https://doi.org/10.1172/JCI133661

• Journal Article Type: Article
• Acceptance Date: Jan 8, 2020
• Online Publication Date: Jan 23, 2020
• Publication Date: May 1, 2020
• Deposit Date: Mar 26, 2020
• Publicly Available Date: Apr 1, 2020
• Journal: Journal of Clinical Investigation
• Print ISSN: 0021-9738
• Electronic ISSN: 1558-8238
• Publisher: American Society for Clinical Investigation
• Peer Reviewed: Peer Reviewed
• Volume: 130
• Issue: 5
• Pages: 2301-2318
• DOI: https://doi.org/10.1172/JCI133661
• Public URL: https://nottingham-repository.worktribe.com/output/3794279
• Publisher URL: https://www.jci.org/articles/view/133661