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Myelin Oligodendrocyte Glycoprotein MOG35-55 Induced Experimental Autoimmune Encephalomyelitis EAE in C57BL/6 Mice
Published on: April 15, 2014
Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune
Ranjithkumar Rajendran1, Mario Giraldo-Velásquez2, Christine Stadelmann3
1Department of Neurology, University of Giessen, Klinikstrasse 33, Giessen, 35385, Germany.
Abstract:
Fibroblast growth factors (FGFs) exert diverse biological effects by binding and activation of specific fibroblast growth factor receptors (FGFRs). FGFs and FGFRs have been implicated in demyelinating pathologies including multiple sclerosis. In vitro activation of the FGF2/FGFR1 pathway results in downregulation of myelin proteins. FGF1, 2 and 9 have been shown to be involved in the pathology of multiple sclerosis. Recent studies on the function of oligodendroglial FGFR1 in a model of toxic demyelination showed that deletion of FGFR1 led to increased remyelination and preservation of axonal density and an increased number of mature oligodendrocytes. In the present study the in vivo function of oligodendroglial FGFR1 was characterized using an oligodendrocyte-specific genetic approach in the most frequently used model of multiple sclerosis the MOG35-55 -induced EAE. Oligodendroglial FGFR1 deficient mice (referred to as Fgfr1ind-/- ) showed a significantly ameliorated disease course in MOG35-55 -induced EAE. Less myelin and axonal loss, and reduced lymphocyte and macrophage/microglia infiltration were found in Fgfr1ind-/- mice. The reduction in disease severity in Fgfr1ind-/- mice was accompanied by ERK/AKT phosphorylation, and increased expression of BDNF and TrkB. Reduced proinflammatory cytokine and chemokine expression was seen in Fgfr1ind-/- mice compared with control mice. Considering that FGFR inhibitors are used in cancer trials, the oligodendroglial FGFR1 pathway may provide a new target for therapy in multiple sclerosis.
Insights
Removing fibroblast growth factor receptor 1 (FGFR1) in oligodendrocytes improved multiple sclerosis models. This FGFR1 deficiency reduced myelin and axonal loss, suggesting FGFR1 as a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Fibroblast growth factors (FGFs) and their receptors (FGFRs) play roles in various biological processes.
- FGFs and FGFRs are implicated in demyelinating diseases like multiple sclerosis (MS).
- Previous in vitro studies showed FGF2/FGFR1 pathway activation downregulates myelin proteins.
Purpose of the Study:
- To investigate the in vivo role of oligodendroglial FGFR1 in a mouse model of multiple sclerosis.
- To determine if targeting oligodendroglial FGFR1 can ameliorate disease progression and pathology in experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- Utilized an oligodendrocyte-specific genetic approach to create FGFR1-deficient mice (Fgfr1ind-/-).
- Induced experimental autoimmune encephalomyelitis (EAE) using MOG35-55 in wild-type and Fgfr1ind-/- mice.
- Assessed disease severity, demyelination, axonal damage, immune cell infiltration, and molecular signaling pathways.
Main Results:
- Fgfr1ind-/- mice exhibited significantly milder EAE disease courses compared to controls.
- Reduced myelin and axonal loss were observed in Fgfr1ind-/- mice.
- Decreased infiltration of lymphocytes and macrophages/microglia, along with reduced pro-inflammatory cytokine expression, were noted in deficient mice.
- Increased ERK/AKT phosphorylation and expression of BDNF and TrkB were associated with disease amelioration.
Conclusions:
- Oligodendroglial FGFR1 plays a detrimental role in the MOG35-55-induced EAE model.
- Deletion of oligodendroglial FGFR1 promotes neuroprotection, remyelination, and reduces inflammation.
- The oligodendroglial FGFR1 pathway represents a promising therapeutic target for multiple sclerosis treatment.
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