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Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation.

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.

SUBMITTER: Reglero-Real N

PROVIDER: S-EPMC8459396 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation.

Reglero-Real Natalia N Pérez-Gutiérrez Lorena L Yoshimura Azumi A Rolas Loïc L Garrido-Mesa José J Barkaway Anna A Pickworth Catherine C Saleeb Rebeca S RS Gonzalez-Nuñez Maria M Austin-Williams Shani N SN Cooper Dianne D Vázquez-Martínez Laura L Fu Tao T De Rossi Giulia G Golding Matthew M Voisin Mathieu-Benoit MB Boulanger Chantal M CM Kubota Yoshiaki Y Muller William A WA Tooze Sharon A SA Nightingale Thomas D TD Collinson Lucy L Perretti Mauro M Aksoy Ezra E Nourshargh Sussan S

Immunity 20210806 9

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 ...[more]

PMID: 34363750

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Project description:BackgroundUlcerative colitis (UC) is a progressive chronic inflammatory disorder. Neutrophils play a critical role in regulating intestinal mucosal homeostasis in UC. Spleen tyrosine kinase (Syk) is involved in several inflammatory diseases. Here, we evaluated the effects and underlying mechanisms of Syk on neutrophil immune-responses in UC.MethodsSyk expression in the colonic tissues of patients with UC was determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. Colonic biopsies from patients with UC were obtained for single-cell RNA-sequencing. Neutrophils isolated from peripheral blood were pre-treated with R788 (a Syk inhibitor) and gene differences were determined using RNA sequencing. Neutrophil functions were analyzed using qRT-PCR, flow cytometry, and Transwell assay. R788 was administered daily to mice with dextran sulfate sodium (DSS)-induced colitis to verify the effects of Syk on intestinal inflammation.ResultsSyk expression was increased in inflamed mucosa and neutrophils of patients with UC and positively correlated with disease activity. Pharmacological inhibition of Syk in neutrophils decreased the production of pro-inflammatory cytokines, chemokines, neutrophil extracellular traps, reactive oxygen species, and myeloperoxidase. Apoptosis and migration of neutrophils were suppressed by Syk blockade. Syk blockade ameliorated mucosal inflammation in DSS-induced murine colitis by inhibiting neutrophil-associated immune responses. Mechanistically, Syk regulated neutrophil immune-responses via the mammalian target of rapamycin kinase/rubicon-like autophagy enhancer-dependent autophagy pathway.ConclusionsOur findings indicate that Syk facilitates specific neutrophil functional responses to mucosal inflammation in UC, and its inhibition ameliorates mucosal inflammation in DSS-induced murine colitis, suggesting its potential as a novel therapeutic target for UC treatment.

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Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation.

Publications

Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation.

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