Details

Autor(en) / Beteiligte

• 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

Titel

MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane

Ist Teil von

• The Journal of clinical investigation, 2016-11, Vol.126 (11), p.4125-4139

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.