Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
Robert A Benson
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Juliette Hadchouel
Université Paris Cité, INSERM, Paris Cardiovascular Research Center (PARCC), Paris, France
Emanuele Procopio
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
Guillaume Even
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
Julie Vorbe
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
Samira Benadda
Cell and Tissue Imaging Platform, INSERM, CNRS, ERL8252, Centre de Recherche sur l’Inflammation (CRI), Paris, France
Véronique Ollivier
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
Benoit Ho-Tin-Noe
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
Antonino Nicoletti
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France; Department of Cardiology and of Physiology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Nord Val-de-Seine, Site Bichat, Paris, France
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.
