The role of the astrocytic and microglial aryl hydrocarbon receptor in CNS demyelination

Schmid, Susanne

dc.contributor.advisor	Brück, Wolfgang Prof. Dr.
dc.contributor.author	Schmid, Susanne
dc.date.accessioned	2020-11-26T10:43:21Z
dc.date.available	2021-10-29T00:50:15Z
dc.date.issued	2020-11-26
dc.identifier.uri	http://hdl.handle.net/21.11130/00-1735-0000-0005-14FF-6
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-8335
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	610
dc.title	The role of the astrocytic and microglial aryl hydrocarbon receptor in CNS demyelination	de
dc.type	doctoralThesis	de
dc.contributor.referee	Brück, Wolfgang Prof. Dr.
dc.date.examination	2020-10-30
dc.description.abstracteng	The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which plays a key role in the regulation of immune and inflammatory responses. AhR expression in astrocytes and microglia was shown to limit central nervous system (CNS) inflammation. However, little is known about the function of AhR signaling in glial cells. The aim of the present study was to evaluate the role of astrocytic and microglial AhR in CNS demyelination and to investigate the impact of cell-specific AhR deletion on the therapeutic efficacy of laquinimod (LAQ) under cuprizone. Using the cuprizone mouse model of toxic demyelination, GFAP-, Aldh1l1- and CX3CR1-AhR mice were evaluated histologically after 6 weeks of 0.25% cuprizone feeding. Cell-specific deletion of AhR was confirmed by in vitro expression analysis upon stimulation with the AhR-specific ligand FICZ. Mice lacking astrocytic AhR showed a similar number of mature oligodendrocytes compared to littermate controls, while animals with AhR-deleted microglia displayed a significantly higher oligodendrocyte density after cuprizone challenge. Furthermore, cuprizone feeding for 3 weeks revealed more mature oligodendrocytes and less demyelination in CX3CR1-AhR mice. However, cuprizone-induced demyelination, microglial activation and acute axonal damage in the corpus callosum were comparable in all mouse strains and Cre-negative controls after 6 weeks of cuprizone intake. To investigate the effects of astrocyte- and microglia-specific AhR deletion on LAQ efficacy during toxic demyelination, cuprizone-fed mice were treated simultaneously with LAQ. As in control animals, administration of LAQ prevented mature oligodendrocyte apoptosis, demyelination, microglial infiltration and acute axonal damage in all three mouse strains. Using a reporter-based in vitro assay, NF-κB activation was significantly reduced in AhR-deficient astrocytes as compared to controls. Astrocytic NF-κB activity was diminished by LAQ independent of AhR. In conclusion, these data indicate that astrocytic and microglial AhR expression does not play a major role in mediating the cytotoxic effects of cuprizone treatment. Also, I demonstrate here that the efficacy of LAQ during toxic demyelination is independent of glial AhR expression. Nevertheless, given the fact that LAQ suppresses experimental autoimmune encephalomyelitis in an AhR-dependent manner, AhR signaling may offer a potential target for future therapeutic approaches, particularly for inflammatory diseases of the CNS.	de
dc.contributor.coReferee	Flügel, Alexander Prof. Dr.
dc.contributor.thirdReferee	Burfeind, Peter Prof. Dr.
dc.subject.ger	astrocytes	de
dc.subject.ger	microglia	de
dc.subject.ger	CNS demyelination	de
dc.subject.ger	demyelination	de
dc.subject.ger	aryl hydrocarbon receptor	de
dc.subject.ger	AhR	de
dc.subject.ger	cuprizone	de
dc.subject.eng	aryl hydrocarbon receptor	de
dc.subject.eng	astrocytes	de
dc.subject.eng	microglia	de
dc.subject.eng	CNS demyelination	de
dc.subject.eng	cuprizone	de
dc.identifier.urn	urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-14FF-6-1
dc.affiliation.institute	Medizinische Fakultät
dc.subject.gokfull	Biologie (PPN619875151)	de
dc.subject.gokfull	Molekularbiologie {Medizin} (PPN619875186)	de
dc.description.embargoed	2021-10-29
dc.identifier.ppn	1741284317

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