title: Activation of FXR pathway does not alter glial cell function.
abstract: The nuclear receptor farnesoid-X-receptor (FXR; NR1H4) is expressed not only in the liver, gut, kidney and adipose tissue but also in the immune cells. FXR has been shown to confer protection in several animal models of inflammation, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). FXR agonists are currently tested in clinical trials for treatment of human metabolic diseases. The beneficial effect of FXR agonists in EAE suggests that FXR might represent a potential target in inflammatory-demyelinating CNS diseases, such as MS. In MS, oligodendrocytes not only undergo cell death but also contribute to remyelination. This repair mechanism is impaired due to a differentiation block of oligodendroglial progenitor cells. Activation of other nuclear receptors that heterodimerize with FXR promote oligodendroglial differentiation. Therefore, we wanted to address the functional relevance of FXR for glial cells, especially for oligodendroglial differentiation.
  
  
  
  We isolated primary murine oligodendrocytes from FXR-deficient (FXR Ko) and wild-type (WT) mice and determined the effect of FXR deficiency and activation on oligodendroglial differentiation by analysing markers of oligodendroglial progenitor cells (OPCs) and mature oligodendrocytes (OLs) using qRT-PCR and immunocytochemistry. Additionally, we determined whether FXR activation modulates the pro-inflammatory profile of astrocytes or microglia and whether this may subsequently modulate oligodendroglial differentiation. These in vitro studies were complemented by histological analyses of oligodendrocytes in FXR Ko mice.
  
  
  
  FXR is expressed by OPCs and mature oligodendrocytes. However, lack of FXR did not affect oligodendroglial differentiation in vitro or in vivo. Furthermore, activation of FXR using the synthetic agonist GW4064 did not affect oligodendroglial differentiation, remyelination in an ex vivo model or the expression of pro-inflammatory molecules in astrocytes or microglia. Concordantly, no effects of supernatants from macrophages cultured in the presence of GW4064 were observed regarding a possible indirect impact on oligodendroglial differentiation.
  
  
  
  Our data suggest that FXR is dispensable for oligodendroglial differentiation and that FXR agonists, such as GW4064, represent a potential therapeutic approach for MS which specifically targets peripheral immune cells including macrophages but not brain-resident cells, such as oligodendrocytes, astrocytes or microglia.
authors.affiliation: Institute of Neuropathology, University Hospital Münster, 48149, Münster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Department of Neurology, University of Münster, 48149, Münster, Germany.
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Fleck
authors.affiliation: Institute of Neuropathology, University Hospital Münster, 48149, Münster, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Kirchberg
authors.affiliation: Department of Neurology, University of Münster, 48149, Münster, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hucke
authors.affiliation: Department of Neurology, University of Münster, 48149, Münster, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Liebmann
authors.affiliation: Department of Neurology, University of Münster, 48149, Münster, Germany. luisa.klotz@ukmuenster.de.
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.affiliation: Institute of Neuropathology, University Hospital Münster, 48149, Münster, Germany. tanja.kuhlmann@ukmuenster.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D000070798:Nogo Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D007555:Isoxazoles; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D000070798:Nogo Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D000099150:Receptor, Farnesoid X-Activated; C512773:Olig2 protein, mouse; C412815:GW 4064
keywords: Astrocytes; FXR; GW4064; Microglia; Nuclear receptors; Oligodendrocytes