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Science 334 (6063): 1727-1731

Copyright © 2011 by the American Association for the Advancement of Science

The Hedgehog Pathway Promotes Blood-Brain Barrier Integrity and CNS Immune Quiescence

Jorge Ivan Alvarez,1,* Aurore Dodelet-Devillers,1,* Hania Kebir,1 Igal Ifergan,1 Pierre J. Fabre,2 Simone Terouz,1 Mike Sabbagh,1 Karolina Wosik,1 Lyne Bourbonnière,1 Monique Bernard,1 Jack van Horssen,3 Helga E. de Vries,3 Frédéric Charron,2 Alexandre Prat1,{dagger}

Abstract: The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.

1 Neuroimmunology Unit, Center of Excellence in Neuromics, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Faculty of Medicine, Université de Montréal, Montréal, Quebec, H2L 4M1, Canada.
2 Laboratory of Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal and Department of Medicine, Université de Montréal, Montréal, Quebec, H2W 1R7, Canada.
3 Department of Molecular Cell Biology and Immunology, VU Medical Center, 1007 MB Amsterdam, Netherlands.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: a.prat{at}umontreal.ca


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