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: Maren Lindner, Katja Thümmler, Ariel Arthur, Sarah Brunner, Christina Elliott, Daniel McElroy, Hema Mohan, Anna Williams, Julia M Edgar, Cornelia Schuh, Christine Stadelmann, Susan C Barnett, Hans Lassmann, Steve Mücklisch, Manikhandan Mudaliar, Nicole Schaeren-Wiemers, Edgar Meinl, Christopher Linington
• Journal: Brain : a journal of neurology (Brain) Vol. 138 Issue Pt 7 Pg. 1875-93 (Jul 2015) ISSN: 1460-2156 [Electronic] England
• PMID: 25907862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• FGF9 protein, human
• Fgf9 protein, mouse
• Fgf9 protein, rat
• Fibroblast Growth Factor 9

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Astrocytes (metabolism)
• Cells, Cultured
• Demyelinating Diseases (metabolism, pathology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Fibroblast Growth Factor 9 (metabolism)
• Humans
• Immunohistochemistry
• In Situ Hybridization
• Inflammation (metabolism, pathology)
• Male
• Mice
• Microscopy, Fluorescence
• Middle Aged
• Multiple Sclerosis (metabolism, pathology)
• Oligonucleotide Array Sequence Analysis
• Organ Culture Techniques
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Signal Transduction (physiology)