Brain endothelial TAK1 and NEMO safeguard the neurovascular unit.
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.
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Dirk A
DA
Ridder
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany German Research Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany.
Jan
J
Wenzel
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Kristin
K
Müller
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany Center for Systems Neuroscience, 30559 Hannover, Germany.
Kathrin
K
Töllner
Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada.
Xin-Kang
XK
Tong
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Julian C
JC
Assmann
Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
Stijn
S
Stroobants
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Tobias
T
Weber
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Cristina
C
Niturad
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Lisanne
L
Fischer
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Beate
B
Lembrich
Institute of Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany.
Hartwig
H
Wolburg
Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada.
Marilyn
M
Grand'Maison
Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada.
Panayiota
P
Papadopoulos
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
Eva
E
Korpos
Service de Dermatologie, CHR Metz-Thionville, 57100 Thionville, France.
Francois
F
Truchetet
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany.
Dirk
D
Rades
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
Lydia M
LM
Sorokin
Department of Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Marc
M
Schmidt-Supprian
Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada.
Barry J
BJ
Bedell
Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
Manolis
M
Pasparakis
Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
Detlef
D
Balschun
Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
Rudi
R
D'Hooge
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany Center for Systems Neuroscience, 30559 Hannover, Germany.
Wolfgang
W
Löscher
Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada.
Edith
E
Hamel
Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany German Research Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany markus.schwaninger@pharma.uni-luebeck.de.
Markus
M
Schwaninger
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000235:genetics; D005260:Female; D051550:I-kappa B Kinase / Q000378:metabolism; D007184:Incontinentia Pigmenti / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D062793:Occludin / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D062793:Occludin; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D000099151:MAP Kinase Kinase Kinase 7; C514981:NEMO protein, mouse; C568986:Ocln protein, mouse; C496562:Ikbkb protein, mouse