CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation

Clément, M. et al. (2023) CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation. eLife, 12, e84752. (doi: 10.7554/eLife.84752) (PMID:37549051) (PMCID:PMC10431918)

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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 toward 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.

Item Type:Articles
Additional Information:This work received support from multiple funding sources. We acknowledge the financial support from the following organizations: the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université Paris Cité, a MSDAVENIR research grant (project 'Save-Brain'), the French National Research Agency (ANR) through the 'Investments for the future' program (projects 10-LABX-0017 'Inflamex' and DS0404-16-RHUS-00010 'iVASC'). Additionally, the work conducted in Glasgow was supported by the Engineering and Physical Sciences Research Council (EPSRC) grant EP/L014165/1 and the British Heart Foundation (BHF) grant PG/19/84/34771. We would like to acknowledge the Region Ile de France (CORDDIM) for providing doctoral grants to Drs. Andreata and Clement.
Glasgow Author(s) Enlighten ID:Maffia, Professor Pasquale and Benson, Dr Robert
Authors: Clément, M., Andreata, F., Benson, R. A., Hadchouel, J., Procopio, E., Even, G., Vorbe, J., Benadda, S., Ollivier, V., Ho-Tin-Noe, B., Le Borgne, M., Maffia, P., Nicoletti, A., and Caligiuri, G.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN (Online):2050-084X
Published Online:07 August 2023
Copyright Holders:Copyright © Andreata, Clément et al
First Published:First published in eLife 12:e84752
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190739In Situ Nanoparticle Assemblies for Healthcare Diagnostics and Therapy. Reference: 130479Pasquale MaffiaEngineering and Physical Sciences Research Council (EPSRC)EP/L014165/1SII - Immunology & Infection
308639Defining the individual and integrated roles of inflammatory chemokine receptors (iCCRs) in atherosclerosisPasquale MaffiaBritish Heart Foundation (BHF)PG/19/84/34771SCMH - Cardiovascular & Metabolic Health