Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

Natalia Reglero-Real, Lorena Pérez-Gutiérrez, Azumi Yoshimura, Loïc Rolas, José Garrido-Mesa, Anna Barkaway, Catherine Pickworth, Rebeca S. Saleeb, Maria Gonzalez-Nuñez, Shani N. Austin-Williams, Dianne Cooper, Laura Vázquez-Martínez, Tao Fu, Giulia De Rossi, Matthew Golding, Mathieu Benoit Voisin, Chantal M. Boulanger, Yoshiaki Kubota, William A. Muller, Sharon A. ToozeThomas D. Nightingale, Lucy Collinson, Mauro Perretti, Ezra Aksoy, Sussan Nourshargh

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.

Original languageEnglish
Pages (from-to)1989-2004.e9
JournalImmunity
Volume54
Issue number9
DOIs
Publication statusPublished - 2021 Sep 14

Keywords

  • ATG16L1
  • ATG5
  • PECAM-1
  • autophagy
  • diapedesis
  • endothelium
  • extravasation
  • inflammation
  • junctions
  • neutrophils

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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