Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

The Journal of Experimental Medicine
Dirk A RidderMarkus Schwaninger

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.

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Datasets Mentioned

BETA
GM-6001

Methods Mentioned

BETA
PCA
Electron microscopy
ubiquitination
PCAs
transgenic
SMA
FCS
Protein Assay

Software Mentioned

Fiji
LabChart
maze
ANY
mazeVideo Tracking System
ImageJ
Prism GraphPad

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