Universität zu Köln

Wang, Xu, Deckert, Martina, Nishanth, Gopala, Just, Sissy, Waisman, Ari ORCID: 0000-0003-4304-8234, Naumann, Michael ORCID: 0000-0002-8060-2313 and Schlueter, Dirk (2013). Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-kappa B- and STAT1-dependent chemokine production in astrocytes. Acta Neuropathol., 126 (5). S. 711 - 725. NEW YORK: SPRINGER. ISSN 1432-0533

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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 A20(fl/fl) mice) or selectively in astrocytes (GFAP-Cre A20(fl/fl) mice) resulted in more severe EAE as compared to control animals. In Nestin-Cre A20(fl/fl) and GFAP-Cre A20(fl/fl) mice demyelination and recruitment of inflammatory leukocytes were increased as compared to A20(fl/fl) control mice. Importantly, numbers of encephalitogenic CD4(+) T cells producing interferon (IFN)-gamma, interleukin (IL)-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively, as well as mRNA production of IFN-gamma, IL-17, tumor necrosis factor (TNF), GM-CSF, IL-6, CXCL1, CCL2, and CXCL10 were significantly increased in spinal cords of Nestin-Cre A20(fl/fl) and GFAP-Cre A20(fl/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-kappa B) in response to TNF, IL-17, and GM-CSF, and of signal transducer and activator of transcription 1 (STAT1) upon IFN-gamma stimulation. Due to NF-kappa B 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wang, Xu UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Nishanth, Gopala UNSPECIFIED UNSPECIFIED UNSPECIFIED Just, Sissy UNSPECIFIED UNSPECIFIED UNSPECIFIED Waisman, Ari UNSPECIFIED orcid.org/0000-0003-4304-8234 UNSPECIFIED Naumann, Michael UNSPECIFIED orcid.org/0000-0002-8060-2313 UNSPECIFIED Schlueter, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-472888
DOI:	10.1007/s00401-013-1183-9
Journal or Publication Title:	Acta Neuropathol.
Volume:	126
Number:	5
Page Range:	S. 711 - 725
Date:	2013
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-0533
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REGULATORY T-CELLS; MULTIPLE-SCLEROSIS; EXPRESSION; DISRUPTION; TNFAIP3; GENE; CNS; PHOSPHORYLATION; UBIQUITINATION; UBIQUITYLATION Multiple languages Clinical Neurology; Neurosciences; Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47288