title: Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9.
abstract: Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched 'pre-myelinating' MBP+ / PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients.
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK christopher.linington@glasgow.ac.uk.
authors.forename: Maren
authors.initials: M
authors.lastname: Lindner
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Thümmler
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
authors.forename: Ariel
authors.initials: A
authors.lastname: Arthur
authors.affiliation: 2 Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Brunner
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Elliott
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: McElroy
authors.affiliation: 3 Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Hema
authors.initials: H
authors.lastname: Mohan
authors.affiliation: 4 MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Williams
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Edgar
authors.affiliation: 5 Centre for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schuh
authors.affiliation: 6 Department of Neuropathology, Georg August University, Göttingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Barnett
authors.affiliation: 5 Centre for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: 7 Department of Computer Science, Chemnitz University of Technology, Chemnitz, Germany.
authors.forename: Steve
authors.initials: S
authors.lastname: Mücklisch
authors.affiliation: 8 Glasgow Polyomics, College of Medical, Veterinary and Life Science, University of Glasgow, UK.
authors.forename: Manikhandan
authors.initials: M
authors.lastname: Mudaliar
authors.affiliation: 2 Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schaeren-Wiemers
authors.affiliation: 3 Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
authors.affiliation: 1 Institute of Infection, Immunity and Inflammation, University of Glasgow, UK christopher.linington@glasgow.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Linington
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C496459:FGF9 protein, human; C496460:Fgf9 protein, mouse; C496461:Fgf9 protein, rat; D051525:Fibroblast Growth Factor 9
keywords: FGF; chemokines; inflammation; multiple sclerosis (MS); remyelination