Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

Author:

Ridder Dirk A.1,Wenzel Jan12,Müller Kristin1,Töllner Kathrin34,Tong Xin-Kang5,Assmann Julian C.1,Stroobants Stijn6,Weber Tobias1,Niturad Cristina1,Fischer Lisanne1,Lembrich Beate1,Wolburg Hartwig7,Grand’Maison Marilyn5,Papadopoulos Panayiota5,Korpos Eva8,Truchetet Francois9,Rades Dirk1,Sorokin Lydia M.8,Schmidt-Supprian Marc10,Bedell Barry J.5,Pasparakis Manolis11,Balschun Detlef6,D’Hooge Rudi6,Löscher Wolfgang34,Hamel Edith5,Schwaninger Markus12

Affiliation:

1. Institute of Experimental and Clinical Pharmacology and Toxicology and Department of Radiation Oncology, University of Lübeck, 23562 Lübeck, Germany

2. German Research Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany

3. Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany

4. Center for Systems Neuroscience, 30559 Hannover, Germany

5. Montreal Neurological Institute, McGill University, Montreal QC H3A 0G4, Canada

6. Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium

7. Institute of Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany

8. Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany

9. Service de Dermatologie, CHR Metz-Thionville, 57100 Thionville, France

10. Department of Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany

11. Institute for Genetics, University of Cologne, 50674 Cologne, Germany

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Reference81 articles.

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