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

64 Citations (Scopus)

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
Pages (from-to)1184-1198
Number of pages15
JournalBrain
Volume134
Issue number4
DOIs
StatePublished - Apr 1 2011

Fingerprint

Oligodendroglia
Myelin Sheath
Phosphotransferases
Central Nervous System
NF-kappa B
Poisons
Demyelinating Diseases
Neuroglia
EphA5 Receptor
Cuprizone
Central Nervous System Diseases
Schwann Cells
Autoimmunity
Astrocytes
Health

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Raasch, J., Zeller, N., Van Loo, G., Merkler, D., Mildner, A., Erny, D., ... 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

IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system. / Raasch, Jenni; Zeller, Nicolas; Van Loo, Geert; Merkler, Doron; Mildner, Alexander; Erny, Daniel; Knobeloch, Klaus Peter; Bethea, John R.; Waisman, Ari; Knust, Markus; Del Turco, Domenico; Deller, Thomas; Blank, Thomas; Priller, Josef; Brück, Wolfgang; Pasparakis, Manolis; Prinz, Marco.

In: Brain, Vol. 134, No. 4, 01.04.2011, p. 1184-1198.

Research output: Contribution to journalArticle

Raasch, J, Zeller, N, Van Loo, G, Merkler, D, Mildner, A, Erny, D, Knobeloch, KP, Bethea, JR, 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, vol. 134, no. 4, pp. 1184-1198. https://doi.org/10.1093/brain/awq359
Raasch, Jenni ; Zeller, Nicolas ; Van Loo, Geert ; Merkler, Doron ; Mildner, Alexander ; Erny, Daniel ; Knobeloch, Klaus Peter ; Bethea, John R. ; Waisman, Ari ; Knust, Markus ; Del Turco, Domenico ; Deller, Thomas ; Blank, Thomas ; Priller, Josef ; Brück, Wolfgang ; Pasparakis, Manolis ; Prinz, Marco. / IκB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-κB in the central nervous system. In: Brain. 2011 ; Vol. 134, No. 4. pp. 1184-1198.
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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.",
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