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Acta Neuropathologica
Erschienen in: Acta Neuropathologica 5/2013

01.11.2013 | Original Paper

Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-κB- and STAT1-dependent chemokine production in astrocytes

verfasst von: Xu Wang, Martina Deckert, Nguyen Thi Xuan, Gopala Nishanth, Sissy Just, Ari Waisman, Michael Naumann, Dirk Schlüter

Erschienen in: Acta Neuropathologica | Ausgabe 5/2013

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Abstract

Single-nucleotide polymorphisms in the tumor necrosis factor, alpha-induced protein 3 gene, which encodes the ubiquitin-modifying protein A20, are linked to susceptibility to multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS). Since it is unresolved how A20 regulates MS pathogenesis, we examined its function in a murine model of MS, namely experimental autoimmune encephalomyelitis (EAE). Deletion of A20 in neuroectodermal cells (astrocytes, neurons, and oligodendrocytes; Nestin-Cre A20fl/fl mice) or selectively in astrocytes (GFAP-Cre A20fl/fl mice) resulted in more severe EAE as compared to control animals. In Nestin-Cre A20fl/fl and GFAP-Cre A20fl/fl mice demyelination and recruitment of inflammatory leukocytes were increased as compared to A20fl/fl control mice. Importantly, numbers of encephalitogenic CD4+ T cells producing interferon (IFN)-γ, interleukin (IL)-17, and granulocyte–macrophage colony-stimulating factor (GM-CSF), respectively, as well as mRNA production of IFN-γ, IL-17, tumor necrosis factor (TNF), GM-CSF, IL-6, CXCL1, CCL2, and CXCL10 were significantly increased in spinal cords of Nestin-Cre A20fl/fl and GFAP-Cre A20fl/fl mice, respectively. Compared to A20-sufficient astrocytes, A20-deficient astrocytes displayed stronger activation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) in response to TNF, IL-17, and GM-CSF, and of signal transducer and activator of transcription 1 (STAT1) upon IFN-γ stimulation. Due to NF-κB and STAT1 hyperactivation, A20-deficient astrocytes produced significantly more chemokines in response to these key encephalitogenic cytokines of autoimmune CD4+ T cells resulting in an amplification of CD4+ T cell recruitment to the CNS. Thus, astrocytic A20 is an important inhibitor of autoimmune-mediated demyelination in the CNS.
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Metadaten
Titel
Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-κB- and STAT1-dependent chemokine production in astrocytes
verfasst von
Xu Wang
Martina Deckert
Nguyen Thi Xuan
Gopala Nishanth
Sissy Just
Ari Waisman
Michael Naumann
Dirk Schlüter
Publikationsdatum
01.11.2013
Verlag
Springer Berlin Heidelberg
Erschienen in
Acta Neuropathologica / Ausgabe 5/2013
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-013-1183-9

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