Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG35-55-Induced EAE.

Ranjithkumar Rajendran,Vinothkumar Rajendran,Christine Stadelmann,Fynn Gurski,Mario Giraldo-Velasquez,Srikanth Karnati,Martin Berghoff,Fevronia-Foivi Megalofonou

doi:10.3390/ijms22179495

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind−/−) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind−/− mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind−/−mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1ind−/− mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind−/− mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS) associated with oligodendrocyte injury, demyelination, and degeneration of axons [1]
To assess the effects of oligodendrocyte-specific deletion of FGFR1 in the spinal cord, we previously reported a reduction in CD3(+) T cells, B220(+) B cells and Mac3(+)
Cell-specific deletion of FGFR1 in oligodendrocytes exhibited less axonal damage, less myelin loss, and decreased inflammation in EAE. These effects in the cerebellum were associated by changes in Fibroblast growth factors (FGFs)/FGFR signaling, increased BDNF/TrkB

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS) associated with oligodendrocyte injury, demyelination, and degeneration of axons [1]. As a consequence of demyelination, oligodendrocytes differentiate, proliferate, and migrate to repair damaged myelin sheaths [2,3,4]. This repair mechanism is effective in early stages of MS, but it deteriorates with disease progression [5,6,7,8,9]. An increased number of FGF1/2+ macrophages and astrocytes were observed in and around active lesions in the cerebral cortex and periventricular white matter; FGFR1 was upregulated in oligodendrocyte progenitor cells (OPC) in active lesions and around chronic lesions [12,13].

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