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Kurz, Angela R. M.; Pruenster, Monika; Rohwedder, Ina; Ramadass, Mahalakshmi; Schäfer, Kerstin; Harrison, Ute; Gouveia, Gabriel; Nussbaum, Claudia; Immler, Roland; Wiessner, Johannes R.; Margraf, Andreas; Lim, Dae-Sik; Walzog, Barbara; Dietzel, Steffen; Moser, Markus; Klein, Christoph; Vestweber, Dietmar; Haas, Rainer; Catz, Sergio D.; Sperandio, Markus (2016): MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane. In: Journal of Clinical investigation, Vol. 126, No. 11: pp. 4125-4139
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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.