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

  1. Francesco Andreata
  2. Marc Clément
  3. Robert A Benson
  4. Juliette Hadchouel
  5. Emanuele Procopio
  6. Guillaume Even
  7. Julie Vorbe
  8. Samira Benadda
  9. Véronique Ollivier
  10. Benoit Ho-Tin-Noe
  11. Marie Le Borgne
  12. Pasquale Maffia
  13. Antonino Nicoletti
  14. Giuseppina Caligiuri  Is a corresponding author
  1. Laboratory for Vascular Translational Science, France
  2. University of Glasgow, United Kingdom
  3. Université Paris Cité, INSERM, France
  4. 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

  1. Francesco Andreata

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
  2. Marc Clément

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6479-8360
  3. Robert A Benson

    Institute of Infection, Immunology and Inflammation, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    No competing interests declared.
  4. Juliette Hadchouel

    INSERM UMR_S1155, Université Paris Cité, INSERM, Paris, France
    Competing interests
    No competing interests declared.
  5. Emanuele Procopio

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
  6. Guillaume Even

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
  7. Julie Vorbe

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
  8. Samira Benadda

    Centre de recherche sur l'inflammation, Université de Paris, INSERM U1149, CNRS ERL8252, Paris, France
    Competing interests
    No competing interests declared.
  9. Véronique Ollivier

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
  10. Benoit Ho-Tin-Noe

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
  11. Marie Le Borgne

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3439-4867
  12. Pasquale Maffia

    Institute of infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3926-4225
  13. Antonino Nicoletti

    Laboratory for Vascular Translational Science, Paris, France
    Competing interests
    Antonino Nicoletti, is an inventorn patents filed (Improved CD31 peptides" PCT/EP2013/062806) related to the work presented in this manuscript. No other potential conflicts of interest relevant to this article exist.".
  14. Giuseppina Caligiuri

    Laboratory for Vascular Translational Science, Paris, France
    For correspondence
    giuseppina.caligiuri@inserm.fr
    Competing interests
    Giuseppina Caligiuri, is an inventor on patents filed (Improved CD31 peptides" PCT/EP2013/062806) related to the work presented in this manuscript. No other potential conflicts of interest relevant to this article exist.".
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4973-2205

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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  1. Francesco Andreata
  2. Marc Clément
  3. Robert A Benson
  4. Juliette Hadchouel
  5. Emanuele Procopio
  6. Guillaume Even
  7. Julie Vorbe
  8. Samira Benadda
  9. Véronique Ollivier
  10. Benoit Ho-Tin-Noe
  11. Marie Le Borgne
  12. Pasquale Maffia
  13. Antonino Nicoletti
  14. Giuseppina Caligiuri
(2023)
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

Share this article

https://doi.org/10.7554/eLife.84752

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