IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system

Jenni Raasch, Nicolas Zeller, Geert Van Loo, Doron Merkler, Alexander Mildner, Daniel Erny, Klaus Peter Knobeloch, John R. Bethea, Ari Waisman, Markus Knust, Domenico Del Turco, Thomas Deller, Thomas Blank, Josef Priller, Wolfgang Brück, Manolis Pasparakis, Marco Prinz

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

The IκB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IκB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during health and disease is largely unknown. Surprisingly, we found that brain-specific IκB kinase 2 expression is dispensable for proper myelin assembly and repair in the central nervous system, but instead plays a fundamental role for the loss of myelin in the cuprizone model. During toxic demyelination, inhibition of nuclear factor kappa B activation by conditional ablation of IκB kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, IκB kinase 2 depletion in astrocytes, but not in oligodendrocytes, was sufficient to protect mice from myelin loss. Our results reveal a crucial role of glial cell-specific IκB kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting IκB kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases.

Original languageEnglish (US)
Pages (from-to)1184-1198
Number of pages15
JournalBrain
Volume134
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • cuprizone
  • demyelination
  • glia
  • multiple sclerosis
  • NF-κB
  • oligodendrocyte
  • remyelination

ASJC Scopus subject areas

  • Clinical Neurology

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  • Cite this

    Raasch, J., Zeller, N., Van Loo, G., Merkler, D., Mildner, A., Erny, D., Knobeloch, K. P., Bethea, J. R., Waisman, A., Knust, M., Del Turco, D., Deller, T., Blank, T., Priller, J., Brück, W., Pasparakis, M., & Prinz, M. (2011). IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system. Brain, 134(4), 1184-1198. https://doi.org/10.1093/brain/awq359