Polarizing receptor activation dissociates fibroblast growth factor 2 mediated inhibition of myelination from its neuroprotective potential.
- Thümmler K Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK. kat.thuemmler@gmail.com.
- Rom E ProCore Bio Med Ltd., Weizmann Science Park, 70400, Ness Ziona, Israel.
- Zeis T Neurobiology Laboratory, University Hospital Basel, University of Basel, 4031, Basel, Switzerland.
- Lindner M Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
- Brunner S Neurobiology Laboratory, University Hospital Basel, University of Basel, 4031, Basel, Switzerland.
- Cole JJ Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
- Arseni D Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
- Mücklisch S Department of Computer Science, Chemnitz University of Technology, 09111, Chemnitz, Germany.
- Edgar JM Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
- Schaeren-Wiemers N Neurobiology Laboratory, University Hospital Basel, University of Basel, 4031, Basel, Switzerland.
- Yayon A ProCore Bio Med Ltd., Weizmann Science Park, 70400, Ness Ziona, Israel.
- Linington C Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
- 2019-12-21
Published in:
- Acta neuropathologica communications. - 2019
Multiple sclerosis and Neuroinflammation
Neuroinflammation
Neuroprotection
Oligodendrocyte
Remyelination
Animals
Astrocytes
Fibroblast Growth Factor 2
Humans
Mice
Mice, Inbred C57BL
Multiple Sclerosis
Nerve Fibers, Myelinated
Neuroprotection
Rats
Rats, Sprague-Dawley
Receptor, Fibroblast Growth Factor, Type 1
English
Fibroblast growth factor (FGF) signaling contributes to failure of remyelination in multiple sclerosis, but targeting this therapeutically is complicated by its functional pleiotropy. We now identify FGF2 as a factor up-regulated by astrocytes in active inflammatory lesions that disrupts myelination via FGF receptor 2 (FGFR2) mediated activation of Wingless (Wnt) signaling; pharmacological inhibition of Wnt being sufficient to abrogate inhibition of myelination by FGF2 in tissue culture. Using a novel FGFR1-selective agonist (F2 V2) generated by deleting the N-terminal 26 amino acids of FGF2 we demonstrate polarizing signal transduction to favor FGFR1 abrogates FGF mediated inhibition of myelination but retains its ability to induce expression of pro-myelinating and immunomodulatory factors that include Cd93, Lif, Il11, Hbegf, Cxcl1 and Timp1. Our data provide new insights into the mechanistic basis of remyelination failure in MS and identify selective activation of FGFR1 as a novel strategy to induce a neuroprotective signaling environment in multiple sclerosis and other neurological diseases.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s40478-019-0864-6
- PMID 31856924
- Persistent URL
- https://sonar.ch/global/documents/111450
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