Abstract

Extravasation of neutrophils from postcapillary venules into inflamed tissue is a crucial step during the inflammatory response. Within this process, neutrophils migrate across the endothelium and subsequently need to penetrate the perivascular basement membrane. The precise regulation of both steps is not fully understood, yet. By using multiphoton intravital microscopy and immunofluorescence staining we identified mammalian sterile 20-like kinase 1 (MST1) as a key player for the migration of neutrophils through the perivascular basement membrane. Mst1 knock out neutrophils (Mst1-/-) persist between the endothelium and the basement membrane of inflamed murine cremaster muscle venules and fail to migrate into inflamed tissue. Mst1-/- neutrophils also fail to extravasate from gastric submucosal vessels in a murine Helicobacter pylori infection model. Mechanistically, impaired extravasation of Mst1-/- neutrophils was accompanied by defective translocation of VLA-3, VLA-6, and neutrophil elastase from intracellular vesicles to the neutrophil surface, a requirement for neutrophils to penetrate the basement membrane. Taken together, our findings identify MST1 as a critical regulator of neutrophil transmigration and emphasize the importance of MST1-dependent vesicle trafficking for the recruitment process.