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

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 disease

The role of the IKK/NF-kappaB pathway in myelination, de- and remyelination of the central nervous system

In der vorliegenden wissenschaftlichen Arbeit ging es darum, die funktionelle Rolle des klassischen NF-kappaB Signalweges bei der Entwicklung (Myelinisierung), Schädigung (Demyelinisierung) und Regeneration (Remyelinisierung) des Myelins im zentralen Nervensystem (ZNS) aufzuklären. De- und Remyelinisierung sind Prozesse, wie sie bei Erkrankungen des Myelins, z.B. bei der Multiplen Sklerose (MS), auftreten.Die MS ist eine autoimmune Demyelinisierungserkrankung mit heterogenem klinischen, pathologischen und immunologischen Phänotyp. Die meisten Erkenntnisse über die Entstehung der MS beruhen auf dem T-Zell-vermittelten Tiermodell der experimentellen autoimmunen Enzephalomyelitis (EAE). Die Beteiligung der gehirneigenen Immunzellen (Astrozyten und Mikroglia) sowie der myelinbildenden Oligodendrozyten an der Entstehung der MS ist dagegen noch kaum untersucht.Der nukleäre Faktor kappaB (NF-kappaB) ist ein wichtiger Mediator des Immunsystems. Daneben ist er u.a. an zahlreichen Prozessen im ZNS beteiligt, z.B an der neuronalen Plastizität, dem Überleben von Neuronen und Gliazellen, sowie an autoimmunen Entzündungen des Gehirns. Im peripheren Nervensystem (PNS) ist der Signalweg essentiell für die Myelinbildung durch Schwannzellen. Die Funktion von NF-kappaB bei der Myelinisierung des ZNS war bisher ungeklärt.Im Rahmen der vorliegenden Arbeit konnte ein pathogenetischer Einfluss des klassischen NF-kappaB Signalweges via IkappaB Kinase 2 (IKK2) auf die Cuprizon-induzierte Oligodendrozytenschädigung identifiziert werden: Die Inhibition des NF-kappaB Signalweges durch eine ZNS-spezifische IKK2-Deletion wirkt sich in diesem Modell protektiv auf Oligodendrozyten aus. Bemerkenswerterweise hat eine Oligodendrozyten-spezifische Inhibition der NF-kappaB Aktivierung keine Auswirkungen auf die toxische Demyelinisierung. Das bedeutet, dass 1.) in diesen Zellen IKK2 keine pro- oder antiapoptotische Wirkung vermittelt, und 2.) die myelinerhaltende Wirkung der IKK2-Deletion über andere neuroektodermale Zellen vermittelt wird. Bei der Myelinisierung während der Entwicklung und bei der Remyelinisierung nach einem toxisch induzierten Myelinschaden wurde eine essentielle Rolle des klassischen NF-kappaB Signalweges in Gehirnzellen ausgeschlossen. Der Signalweg könnte sich daher als ein vielversprechendes neues Angriffsziel für eine Therapieentwicklung bei der MS und anderen Demyelinisierungserkrankungen des ZNS erweisen

Type I interferon receptor signalling is induced during demyelination while its function for myelin damage and repair is redundant

The type I interferons, interferon-beta and alpha (IFN-beta, IFN-alpha), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-beta as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated. Myelin damage, astrocytic and microglia response, however, were not significantly reduced in the absence of IFNAR1. Furthermore, motor skills of IFNAR1-deficient animals during non-immune demyelination were unaltered. Finally, myelin recovery was found to be independent from endogenous IFNAR signalling, indicating a redundant role of this receptor for non-inflammatory myelin damage and repair

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

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

USP18 lack in microglia causes destructive interferonopathy of the mouse brain

Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy

Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system

The action of type I interferons in the central nervous system (CNS) during autoimmunity is largely unknown. Here, we demonstrate elevated interferon beta concentrations in the CNS, but not blood, of mice with experimental autoimmune encephalomyelitis (EAE), a model for CNS autoimmunity. Furthermore, mice devoid of the broadly expressed type I IFN receptor (IFNAR) developed exacerbated clinical disease accompanied by a markedly higher inflammation, demyelination, and lethality without shifting the T helper 17 (Th17) or Th1 cell immune response. Whereas adoptive transfer of encephalitogenic T cells led to enhanced disease in Ifnar1(-/-) mice, newly created conditional mice with B or T lymphocyte-specific IFNAR ablation showed normal EAE. The engagement of IFNAR on neuroectodermal CNS cells had no protective effect. In contrast, absence of IFNAR on myeloid cells led to severe disease with an enhanced effector phase and increased lethality, indicating a distinct protective function of type I IFNs during autoimmune inflammation of the CNS