Journal of Experimental Medicine 2015-09-21

Brain endothelial TAK1 and NEMO safeguard the neurovascular unit.

Dirk A Ridder, Jan Wenzel, Kristin Müller, Kathrin Töllner, Xin-Kang Tong, Julian C Assmann, Stijn Stroobants, Tobias Weber, Cristina Niturad, Lisanne Fischer, Beate Lembrich, Hartwig Wolburg, Marilyn Grand'Maison, Panayiota Papadopoulos, Eva Korpos, Francois Truchetet, Dirk Rades, Lydia M Sorokin, Marc Schmidt-Supprian, Barry J Bedell, Manolis Pasparakis, Detlef Balschun, Rudi D'Hooge, Wolfgang Löscher, Edith Hamel, Markus Schwaninger

Index: J. Exp. Med. 212 , 1529-49, (2015)

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Abstract

Inactivating mutations of the NF-κB essential modulator (NEMO), a key component of NF-κB signaling, cause the genetic disease incontinentia pigmenti (IP). This leads to severe neurological symptoms, but the mechanisms underlying brain involvement were unclear. Here, we show that selectively deleting Nemo or the upstream kinase Tak1 in brain endothelial cells resulted in death of endothelial cells, a rarefaction of brain microvessels, cerebral hypoperfusion, a disrupted blood-brain barrier (BBB), and epileptic seizures. TAK1 and NEMO protected the BBB by activating the transcription factor NF-κB and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-κB-independent manner by reducing oxidative damage. Our data identify crucial functions of inflammatory TAK1-NEMO signaling in protecting the brain endothelium and maintaining normal brain function, thus explaining the neurological symptoms associated with IP. © 2015 Ridder et al.