| First Author | Winneberger J | Year | 2021 |
| Journal | Brain Behav Immun | Volume | 93 |
| Pages | 277-287 | PubMed ID | 33388423 |
| Mgi Jnum | J:311749 | Mgi Id | MGI:6780324 |
| Doi | 10.1016/j.bbi.2020.12.026 | Citation | Winneberger J, et al. (2021) Platelet endothelial cell adhesion molecule-1 is a gatekeeper of neutrophil transendothelial migration in ischemic stroke. Brain Behav Immun 93:277-287 |
| abstractText | RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSION: 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. |
