Platelet endothelial cell adhesion molecule-1 is a gatekeeper of neutrophil transendothelial migration in ischemic stroke

• Published in: Brain, behavior, and immunity Vol. 93; pp. 277 - 287
• Main Authors: Winneberger, Jack, Schöls, Sebastian, Lessmann, Katrin, Rández-Garbayo, Javier, Bauer, Alexander T., Mohamud Yusuf, Ayan, Hermann, Dirk M., Gunzer, Matthias, Schneider, Stefan W., Fiehler, Jens, Gerloff, Christian, Gelderblom, Mathias, Ludewig, Peter, Magnus, Tim
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.03.2021
• Subjects: Animal models of human disease; Animals; Blood-brain barrier; Brain Ischemia; Cell adhesion molecules; Cell Movement; Cerebrovascular disease; Endothelial Cells; Endothelium, Vascular; Ischemic Stroke; Leukocytes; Male; Mice; Mice, Knockout; Neutrophils; Platelet Endothelial Cell Adhesion Molecule-1; Postischemic inflammation; Stroke; Trans-endothelial migration; Transendothelial and Transepithelial Migration; PECAM-1; BBB; LBRC; MRI; Postischemic inflammation; Ischemic stroke; Leukocytes; MPO; ICAM1; Cell adhesion molecules; Trans-endothelial migration; Animal models of human disease; Blood-brain barrier; ASL; WT; Cerebrovascular disease; DAPI; VLA-4; OGD; CAM; MMP; CEACAM1; ROS; TEM; tMCAO
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2020.12.026

•Loss of PECAM-1 improves outcome in a mouse model of ischemic stroke.•PECAM-1 increases diapedesis of neutrophils in ischemic stroke in vivo and in vitro.•Blocking anti-PECAM-1 antibodies reduces neutrophil infiltration and infarct volume. Adhesion molecules are key elements in stroke-induced brain injury by regulating the migration of effector immune cells from the circulation to the lesion site. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an adhesion molecule highly expressed on endothelial cells and leukocytes, which controls the final steps of trans-endothelial migration. A functional role for PECAM-1 in post-ischemic brain injury has not yet been demonstrated. Using genetic Pecam-1 depletion and PECAM-1 blockade using a neutralizing anti-PECAM-1 antibody, we evaluated the role of PECAM-1 mediated trans-endothelial immune cell migration for ischemic injury, delayed brain atrophy, and brain immune cell infiltrates. Trans-endothelial immune cell migration was furthermore evaluated in cultured human cerebral microvascular endothelial cells. Transient middle cerebral artery occlusion (tMCAO) was induced in 10–12-week-old male Pecam-1−/− and Pecam-1+/+ wildtype mice. PECAM-1 levels increased in the ischemic brain tissue due to the infiltration of PECAM-1+ leukocytes. Using magnetic resonance imaging, we observed smaller infarct volume, less edema formation, and less brain atrophy in Pecam-1−/− compared with Pecam-1+/+ wildtype mice. The transmigration of leukocytes, specifical neutrophils, was selectively reduced by Pecam-1−/−, as shown by immune fluorescence and flow cytometry in vivo and transmigration assays in vitro. Importantly, inhibition with an anti-PECAM-1 antibody in wildtype mice decreased neutrophil brain influx and infarct. PECAM-1 controls the trans-endothelial migration of neutrophils in a mouse model of ischemic stroke. Antibody blockade of PECAM-1 after stroke onset ameliorates stroke severity in mice, making PECAM-1 an interesting target to dampen post-stroke neuroinflammation, reduce ischemic brain injury, and enhance post-ischemic brain remodeling.