CEACAM1 Inhibits MMP-9-Mediated Blood-Brain-Barrier Breakdown in a Mouse Model for Ischemic Stroke
Rationale: Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated.
Objective: We sought to identify and characterize the relevance of CEACAM1- expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1-/- and wild type (WT) mice.
Methods and Results: Focal ischemia was induced by temporary occlusion of the middle cerebral artery (tMCAO) with a microfilament. Using magnetic resonance imaging (MRI) and Evans blue permeability assays, we observed increased stroke volumes, BBB breakdown and edema formation, reduction of cerebral perfusion and brain atrophy in Ceacam1-/- mice.This translated into poor performance in neurological scoring and high post stroke-associated mortality. Elevated neutrophil influx, hyperproduction and release of neutrophil-related matrix metalloproteinase (MMP)-9 in Ceacam1-/- mice were confirmed by immune fluorescence, flow cytometry, zymography and stimulation of neutrophils. Importantly, neutralization of MMP-9 activity in Ceacam1-/- mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochemistry of murine and human post-stroke autoptic brains congruently identified abundance of CEACAM1+MMP9+ neutrophils in the ischemic hemispheres.
Conclusions: CEACAM1 controls MMP-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.
- Received February 18, 2013.
- Revision received June 13, 2013.
- Accepted June 18, 2013.