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

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
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Issue Date
2016-11
Language
ENG
Keywords

IN-VIVO; LEUKOCYTE MIGRATION; TRANSENDOTHELIAL MIGRATION; LYMPHOCYTE TRAFFICKING; EXTRACELLULAR-MATRIX; ACTIVATING PROTEIN; GRANULE SECRETION; CELL RECRUITMENT; LAMININ ISOFORMS; NADPH OXIDASE

Citation

JOURNAL OF CLINICAL INVESTIGATION, v.126, no.11, pp.4125 - 4139

ISSN
0021-9738
DOI
10.1172/JCI87043
URI
http://hdl.handle.net/10203/214595
Appears in Collection
BS-Journal Papers(저널논문)
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