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

• Published in: The Journal of clinical investigation 2016-11, Vol.126 (11), p.4125-4139
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Abdominal Muscles - blood supply; Abdominal Muscles - immunology; Analysis; Animals; Apoptosis; Bacterial infections; Basement Membrane - immunology; Biological Transport, Active - genetics; Biological Transport, Active - immunology; Biomedical research; Cell migration; Experiments; Gastric Mucosa - chemistry; Gastric Mucosa - immunology; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - immunology; Humans; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Integrin alpha3beta1 - genetics; Integrin alpha3beta1 - immunology; Integrin alpha6beta1 - genetics; Integrin alpha6beta1 - immunology; Kinases; Leukocyte Elastase - genetics; Leukocyte Elastase - immunology; Lymphocytes; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane, Basement; Mice; Mice, Knockout; Microscopy; Neutrophils; Neutrophils - immunology; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - immunology; Recruitment; Rodents; Secretory Vesicles - genetics; Secretory Vesicles - immunology; Software; Studies; Transendothelial and Transepithelial Migration - genetics; Transendothelial and Transepithelial Migration - immunology; Venules - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI87043

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.