Brain endothelial TAK1 and NEMO safeguard the neurovascular unit.

Autor:	Ridder DA; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Wenzel J; 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., Müller K; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Töllner K; Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany Center for Systems Neuroscience, 30559 Hannover, Germany., Tong XK; Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada., Assmann JC; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Stroobants S; Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium., Weber T; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Niturad C; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Fischer L; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Lembrich B; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Wolburg H; Institute of Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany., Grand'Maison M; Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada., Papadopoulos P; Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada., Korpos E; Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany., Truchetet F; Service de Dermatologie, CHR Metz-Thionville, 57100 Thionville, France., Rades D; Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany., Sorokin LM; Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany., Schmidt-Supprian M; Department of Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Bedell BJ; Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada., Pasparakis M; Institute for Genetics, University of Cologne, 50674 Cologne, Germany., Balschun D; Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium., D'Hooge R; Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium., Löscher W; Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany Center for Systems Neuroscience, 30559 Hannover, Germany., Hamel E; Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada., Schwaninger M; 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.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2015 Sep 21; Vol. 212 (10), pp. 1529-49. Date of Electronic Publication: 2015 Sep 07.
DOI:	10.1084/jem.20150165
Abstrakt:	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.)
Databáze:	MEDLINE
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