TY - JOUR
T1 - Brain endothelial TAK1 and NEMO safeguard the neurovascular unit
AU - Ridder, Dirk A.
AU - Wenzel, Jan
AU - Müller, Kristin
AU - Töllner, Kathrin
AU - Tong, Xin Kang
AU - Assmann, Julian C.
AU - Stroobants, Stijn
AU - Weber, Tobias
AU - Niturad, Cristina
AU - Fischer, Lisanne
AU - Lembrich, Beate
AU - Wolburg, Hartwig
AU - Grand'Maison, Marilyn
AU - Papadopoulos, Panayiota
AU - Korpos, Eva
AU - Truchetet, Francois
AU - Rades, Dirk
AU - Sorokin, Lydia M.
AU - Schmidt-Supprian, Marc
AU - Bedell, Barry J.
AU - Pasparakis, Manolis
AU - Balschun, Detlef
AU - D'Hooge, Rudi
AU - Löscher, Wolfgang
AU - Hame, Edith
AU - Schwaninger, Markus
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84951728678&partnerID=8YFLogxK
U2 - 10.1084/jem.20150165
DO - 10.1084/jem.20150165
M3 - Journal articles
C2 - 26347470
AN - SCOPUS:84951728678
SN - 0022-1007
VL - 212
SP - 1529
EP - 1549
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -
