Inflamed venular ECs exhibit an autophagic response that localizes to EC contacts
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EC ATG5 deficiency promotes excessive and faster neutrophil TEM
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Ablation of EC autophagy increases cell surface expression of adhesion molecules
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Non-canonical autophagy operates in inflamed ECs and controls neutrophil migration
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
Keywords
endothelium
junctions
neutrophils
inflammation
extravasation
autophagy
ATG5
ATG16L1
PECAM-1
diapedesis
Data and code availability
This study did not generate or analyze large datasets or codes.