Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

J Exp Med. 2015 Sep 21;212(10):1529-49. doi: 10.1084/jem.20150165. Epub 2015 Sep 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / blood supply*
  • Brain / metabolism
  • Cerebrovascular Circulation / genetics
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Epilepsy / genetics
  • Female
  • I-kappa B Kinase / metabolism
  • Incontinentia Pigmenti / metabolism
  • Incontinentia Pigmenti / pathology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Occludin / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism
  • Transcription Factor RelA / metabolism


  • Intracellular Signaling Peptides and Proteins
  • NEMO protein, mouse
  • Occludin
  • Ocln protein, mouse
  • TNF Receptor-Associated Factor 6
  • Transcription Factor RelA
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7