Putting the squeeze on the blood-brain barrier

Our newest publication is out in Cell Reports. We showed that Th17 and Th1 lymphocytes use different mechanisms to cross the blood-brain barrier – and cause disease – in animal models of multiple sclerosis. Surprisingly, a majority of Th1 cells actually squeeze through the endothelial cell cytoplasm instead of going through gaps between cells. This process requires endothelial caveolae. Part of the agenda for the Lutz lab is building upon these findings for new ways to therapeutically block or enhance blood-brain barrier permeability. A second surprising finding was that caveolae are not involved in the internalization and destruction of large tight junction segments in the living blood-brain barrier.

This work was done during my post-doctoral training in the lab of Dr. Dritan Agalliu at Columbia University Medical Center, with significant guidance on intravital two-photon microscopy from Dr. Sunil Gandhi at University of California, Irvine.  Thanks to excellent collaborators Julian Smith, Dae Hwan (Glenn) Kim, Carl Olson, Kyle Ellefsen, and Jennifer Bates.

Full text can be viewed at the Cell Reports website: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31574-7

New Translational Neuroimmunology Lab @ University of Illinois at Chicago

We are a new lab joining the Department of Anatomy and Cell Biology of the University of Illinois at Chicago College of Medicine (2017).  Our main goal is to identify and repair mechanisms of damage in neuroinflammatory diseases such as multiple sclerosis using cutting-edge genetic and imaging modalities. Contact us if you are interested in working with us!

Study published in Proceedings of the National Academy of Sciences

My co-first-author paper describing a novel role for the Wnt/beta-catenin signaling pathway in protection of blood-brain barrier endothelial cells has been published in Proceedings of the National Academy of Sciences on January 30, 2017 (Lengfeld, Lutz, et. al.). Endothelial cells (ECs) in the CNS form a unique blood–brain barrier (BBB) that is broken down in multiple sclerosis (MS). New therapies are sorely needed to restore BBB function in this disease. The wingless integrated MMTV (Wnt)/β-catenin pathway, which is essential for barrier formation, is activated in CNS ECs in MS and the animal model experimental autoimmune encephalomyelitis. When this pathway is inhibited in ECs before disease onset, mice develop more severe disease, with more immune cells entering the CNS owing to increased levels of proteins that promote interactions of immune cells with blood vessels and caveolar transport across vessels. Our findings suggest that pharmacologic enhancement of Wnt signaling may be helpful to limit BBB damage and CNS immune cell infiltration in MS. This work was conducted at the University of California Irvine and at Columbia University Medical Center.

Figure 1. Endothelial cell Wnt/b-catenin activation protects the neurovascular unit in the EAE model of multiple sclerosis. A) In the absence of Wnt signaling, neuroinflammation is exacerbated by elevated caveolar transcytosis and vascular cell adhesion molecule (VCAM-1) expression. B) Wnt/β-catenin mediated transcription suppresses caveolar transcytosis and VCAM-1 expression, markedly reducing T cell infiltration into the CNS.

View the abstract at: http://www.pnas.org/content/early/2017/01/26/1609905114.abstract