Abstract
Neutrophils need to penetrate the perivascular basement membrane for successful extravasation into inflamed tissue, but this process is incompletely understood. Recent findings have associated mammalian sterile 20-like Kinase 1 (MST1) loss of function with a human primary immunodeficiency disorder, suggesting that MST1 may be involved in immune cell migration. Here, we have shown that MST1 is a critical regulator of neutrophil extravasation during inflammation. Mst1-deficient (Mst1(-/-)) neutrophils were unable to migrate into inflamed murine cremaster muscle venules, instead persisting between the endothelium and the basement membrane. Mst1(-/-) neutrophils also failed to extravasate from gastric submucosal vessels in a murine model of Helicobacter pylori infection. Mechanistically, we observed defective translocation of VLA-3, VLA-6, and neutrophil elastase from intracellular vesicles to the surface of Mst1(-/-) neutrophils, indicating that MST1 is required for this crucial step in neutrophil transmigration. Furthermore, we found that MST1 associates with the Rab27 effector protein synaptotagmin-like protein 1 (JFC1, encoded by Sytl1 in mice), but not Munc13-4, thereby regulating the trafficking of Rab27-positive vesicles to the cellular membrane. Together, these findings highlight a role for MST1 in vesicle trafficking and extravasation in neutrophils, providing an additional mechanistic explanation for the severe immune defect observed in patients with MST1 deficiency.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 0021-9738 |
| Sprache: | Englisch |
| Dokumenten ID: | 43731 |
| Datum der Veröffentlichung auf Open Access LMU: | 27. Apr. 2018, 08:04 |
| Letzte Änderungen: | 04. Nov. 2020, 13:19 |
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