Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation
| Autor: | Jose Garrido-Mesa, Dianne Cooper, Mauro Perretti, Catherine Pickworth, Matthew Golding, Tao Fu, Loïc Rolas, William A. Muller, Lucy M. Collinson, Ezra Aksoy, Maria Gonzalez-Nunez, Mathieu-Benoit Voisin, Thomas D. Nightingale, Natalia Reglero-Real, Laura Vázquez-Martínez, Shani Austin-Williams, Giulia De Rossi, Lorena Pérez-Gutiérrez, Sussan Nourshargh, Chantal M. Boulanger, Sharon A. Tooze, Yoshiaki Kubota, Anna Barkaway, Azumi Yoshimura, Rebeca S. Saleeb |
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| Rok vydání: | 2021 |
| Předmět: |
autophagy
Leukocyte migration endothelium Endothelium PECAM-1 Neutrophils Immunology ATG5 ATG16L1 Inflammation Biology Article Mice 03 medical and health sciences junctions 0302 clinical medicine Leukocyte Trafficking Human Umbilical Vein Endothelial Cells medicine Animals Humans Immunology and Allergy 030304 developmental biology 0303 health sciences Cell adhesion molecule Autophagy diapedesis Transendothelial and Transepithelial Migration Endothelial Cells Cell migration 3. Good health Cell biology Mice Inbred C57BL Chemotaxis Leukocyte Intercellular Junctions Infectious Diseases medicine.anatomical_structure Neutrophil Infiltration medicine.symptom extravasation 030217 neurology & neurosurgery |
| Zdroj: | Immunity |
| ISSN: | 1074-7613 |
| Popis: | Summary 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. Graphical abstract Highlights • Inflamed venular ECs exhibit an autophagic response that localizes to EC contacts • EC ATG5 deficiency promotes excessive and faster neutrophil TEM • Ablation of EC autophagy increases cell surface expression of adhesion molecules • Non-canonical autophagy operates in inflamed ECs and controls neutrophil migration Transendothelial cell migration (TEM) is a vital step in neutrophil infiltration of tissues, but the molecular basis of its cessation is unclear. Reglero-Real et al. show that in inflamed tissues, endothelial cell autophagy remodels junctional architecture and acts as a negative regulator of neutrophil TEM. |
| Databáze: | OpenAIRE |
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