CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation
- Laboratory for Vascular Translational Science, France
- University of Glasgow, United Kingdom
- Université Paris Cité, INSERM, France
- Université de Paris, INSERM U1149, CNRS ERL8252, France
Abstract
Effective neutrophil migration to sites of inflammation is crucial for host immunity. A coordinated cascade of steps allows intravascular leukocytes to counteract the shear stress, transmigrate through the endothelial layer and move towards the extravascular, static environment. Those events are tightly orchestrated by integrins but, while the molecular mechanisms leading to their activation have been characterized, the regulatory pathways promoting their detachment remain elusive. In light of this, it has long been known that Platelet-Endothelial Cell Adhesion Molecule (Pecam1, also known as CD31) deficiency blocks leukocyte transmigration at the level of the outer vessel wall, yet the associated cellular defects are controversial. In this study, we combined an unbiased proteomic study with in vitro and in vivo single-cell tracking in mice to study the dynamics and role of CD31 during neutrophil migration. We found that CD31 localizes to the uropod of migrating neutrophils along with closed β2-integrin and is required for essential neutrophil actin/integrin polarization. Accordingly, the uropod of Pecam1-/- neutrophils is unable to detach from the extracellular matrix, while antagonizing integrin binding to extracellular matrix components rescues this in vivo migratory defect. Conversely, we showed that sustaining CD31 co-signaling actively favors uropod detachment and effective migration of extravasated neutrophils to sites of inflammation in vivo. Altogether, our results suggest that CD31 acts as a molecular rheostat controlling integrin-mediated adhesion at the uropod of egressed neutrophils thereby triggering their detachment from the outer vessel wall to reach the inflammatory sites.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-5.
Article and author information
Author details
Giuseppina Caligiuri
Funding
MSDAVENIR (SAVE-Brain)
- Antonino Nicoletti
Agence Nationale de la Recherche (10-LABX-0017 Inflamex"")
- Marc Clément
Agence Nationale de la Recherche (DS0404-16-RHUS-00010 iVASC"")
- Giuseppina Caligiuri
Engineering and Physical Sciences Research Council (grant EP/L014165/1)
- Pasquale Maffia
British Heart Foundation (PG/19/84/34771)
- Pasquale Maffia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All the investigations were conformed to the directive 2010/63/EU of the European Parliament and formal approval was granted by the local Animal Ethics Committee (Comité d'étique Bichat-Debré, Paris, France).
Copyright
© 2023, Andreata et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation
eLife 12:e84752.
https://doi.org/10.7554/eLife.84752
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