Sarah Lutz, PhD

In CNS disorders including multiple sclerosis, stroke, cancer, and others, disruption of the blood-brain barrier (BBB) leads to tissue damage and deleterious clinical outcome by enabling infiltration of leukocytes and serum proteins. Barrier function is normally maintained by integrity of tight junctions (restricting paracellular permeability), suppression of caveolar transcytosis (transcellular permeability), and specific ion transporters. Leukocytes actively navigate these structures to access the brain and spinal cord for immunoregulation in health and disease.  We have taken genetic, functional, and in vivo imaging approaches to uncover new aspects of barrier regulation, which have profound implications for disease and recovery, in the middle cerebral artery occlusion (MCAO) model of stroke and the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Using in vivo two photon imaging in transgenic eGFP-Claudin5 mice with fluorescent tight junctions, we have identified dynamic BBB remodeling events that would be impossible to appreciate in fixed tissue preparations. We demonstrate regional anatomic differences in endothelial cell tight junction recycling, which may partially explain the enigmatic preferential vulnerability of the spinal cord to EAE. In MCAO, BBB breakdown occurs in two waves: first transcellular, then paracellular permeability. In EAE, this sequence is reversed. We find that remodeling of TJs precedes the onset of EAE clinical signs in mice and coincides with paracellular BBB leakage. In contrast, transcellular BBB leakage to albumin occurs later, at the peak of disease. Moreover, mice that lack caveolae have reduced EAE clinical severity. These findings suggest that TJ dissolution initiates disease onset, whereas caveolar transcytosis may enhance EAE severity. These findings also have relevance for BBB disruption in multiple neuroinflammatory states.

Blood brain barrier disruption, neurovascular inflammation, and leukocyte infiltration of the nervous system in diseases including COVID-19, multiple sclerosis, aging, and stroke. Focus on CD4+ T cell -endothelial cell interactions.