RRC ID 68009
Author Reglero-Real N, Pérez-Gutiérrez L, Yoshimura A, Rolas L, Garrido-Mesa J, Barkaway A, Pickworth C, Saleeb RS, Gonzalez-Nuñez M, Austin-Williams SN, Cooper D, Vázquez-Martínez L, Fu T, De Rossi G, Golding M, Voisin MB, Boulanger CM, Kubota Y, Muller WA, Tooze SA, Nightingale TD, Collinson L, Perretti M, Aksoy E, Nourshargh S.
Title Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation.
Journal Immunity
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.
Volume 54(9)
Pages 1989-2004.e9
Published 2021-9-14
DOI 10.1016/j.immuni.2021.07.012
PII S1074-7613(21)00298-3
PMID 34363750
PMC PMC8459396
MeSH Animals Autophagy / physiology* Chemotaxis, Leukocyte / physiology Endothelial Cells / pathology Endothelial Cells / physiology* Human Umbilical Vein Endothelial Cells / immunology Human Umbilical Vein Endothelial Cells / pathology Humans Inflammation / immunology Inflammation / pathology Intercellular Junctions / physiology Mice Mice, Inbred C57BL Neutrophil Infiltration / physiology* Neutrophils / physiology Transendothelial and Transepithelial Migration / physiology*
IF 22.553
Mice RBRC00806