Universität zu Köln

Ridder, Dirk A., Wenzel, Jan, Mueller, Kristin, Toellner, Kathrin, Tong, Xin-Kang, Assmann, Julian C., Stroobants, Stijn, Weber, Tobias, Niturad, Cristina, Fischer, Lisanne, Lembrich, Beate, Wolburg, Hartwig, Grand'Maison, Marilyn, Papadopoulos, Panayiota, Korpos, Eva, Truchetet, Francois, Rades, Dirk, Sorokin, Lydia M., Schmidt-Supprian, Marc ORCID: 0000-0002-8543-6166, Bedell, Barry J., Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Balschun, Detlef, D'Hooge, Rudi, Loescher, Wolfgang, Hamel, Edith and Schwaninger, Markus ORCID: 0000-0002-4510-9718 (2015). Brain endothelial TAK1 and NEMO safeguard the neurovascular unit. J. Exp. Med., 212 (10). S. 1529 - 1550. NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-9538

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Abstract

Inactivating mutations of the NF-kappa B essential modulator (NEMO), a key component of NF-kappa B 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-kappa B and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-kappa B-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ridder, Dirk A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wenzel, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Kristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Toellner, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Tong, Xin-Kang UNSPECIFIED UNSPECIFIED UNSPECIFIED Assmann, Julian C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroobants, Stijn UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Niturad, Cristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Lisanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Lembrich, Beate UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolburg, Hartwig UNSPECIFIED UNSPECIFIED UNSPECIFIED Grand'Maison, Marilyn UNSPECIFIED UNSPECIFIED UNSPECIFIED Papadopoulos, Panayiota UNSPECIFIED UNSPECIFIED UNSPECIFIED Korpos, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Truchetet, Francois UNSPECIFIED UNSPECIFIED UNSPECIFIED Rades, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Sorokin, Lydia M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt-Supprian, Marc UNSPECIFIED orcid.org/0000-0002-8543-6166 UNSPECIFIED Bedell, Barry J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Balschun, Detlef UNSPECIFIED UNSPECIFIED UNSPECIFIED D'Hooge, Rudi UNSPECIFIED UNSPECIFIED UNSPECIFIED Loescher, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamel, Edith UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwaninger, Markus UNSPECIFIED orcid.org/0000-0002-4510-9718 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-392780
DOI:	10.1084/jem.20150165
Journal or Publication Title:	J. Exp. Med.
Volume:	212
Number:	10
Page Range:	S. 1529 - 1550
Date:	2015
Publisher:	ROCKEFELLER UNIV PRESS
Place of Publication:	NEW YORK
ISSN:	1540-9538
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; INCONTINENTIA PIGMENTI; ALZHEIMERS-DISEASE; MOUSE MODEL; BARRIER PERMEABILITY; INHIBITION PROTECTS; OXIDATIVE STRESS; AMYLOID-BETA; MICE; CELLS Multiple languages Immunology; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/39278