title: IkappaB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappaB in the central nervous system.
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.
authors.affiliation: Department of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106 Freiburg, Germany.
authors.forename: Jenni
authors.initials: J
authors.lastname: Raasch
authors.forename: Nicolas
authors.initials: N
authors.lastname: Zeller
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.forename: Daniel
authors.initials: D
authors.lastname: Erny
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.forename: John R
authors.initials: JR
authors.lastname: Bethea
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Markus
authors.initials: M
authors.lastname: Knust
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Turco
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Thomas
authors.initials: T
authors.lastname: Blank
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism*; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016328:NF-kappa B; D003471:Cuprizone; D051550:I-kappa B Kinase