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

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.

New developments in the biology of fibroblast growth factors

“…Remyelination is essential for the regenerative response to demyelinating diseases such as MS. Injection of myelin oligodendrocyte glycoprotein peptide (MOG 35–55 ) results in experimental autoimmune encephalomyelitis (EAE), a model for MS. Oligodendrocyte‐specific Fgfr1 deficient mice show a milder disease course, with reduced myelin and axonal loss and reduced lymphocyte and macrophage/microglia infiltration in spinal cord white matter (Rajendran et al, 2018). In the cerebellum, these mice showed reduced myelin and axonal degeneration and reduced inflammatory infiltrates compared to controls (Rajendran, Rajendran, et al, 2021). Thus, cell‐specific inactivation of FGFR1 in oligodendrocytes has anti‐inflammatory and neuroprotective effects, and pharmacological inhibition of FGFRs could have therapeutic benefit (Rajendran, Bottiger, et al, 2021).…”

Interferon Beta-1a versus Combined Interferon Beta-1a and Oligodendrocyte-Specific FGFR1 Deletion in Experimental Autoimmune Encephalomyelitis

“…In MS [ 11 , 25 , 26 ] and EAE models [ 9 , 15 , 16 ], FGF signaling pathways have been shown to be involved in the pathology. In MOG 35-55 -induced EAE, the conditional deletion of FGFR1 or FGFR2 in oligodendrocytes has a number of beneficial effects primarily in the chronic, neurodegenerative phase of EAE.…”

“…1Sor ). The generation of conditional FGFR1 knockout mice was achieved as described earlier [ 15 , 16 ]. Briefly, the genomic DNA was isolated (DirectPCR-Tail, Peqlab, Erlangen, Germany) to identify the deletion of the FGFR1 floxed allele and PLP transgene, and mice were genotyped by PCR.…”

“…In contrast, FGF1 is assumed to promote remyelination [ 11 ]. Oligodendrocyte-specific deletion of FGFR1 in MOG 35-55 -induces experimental autoimmune encephalomyelitis (EAE), an established mouse model for MS, ameliorates the disease’s course, reduces inflammation in demyelinating lesions, and results in less myelin degeneration and higher axonal density [ 15 , 16 ]. These effects were accompanied by the increased phosphorylation of ERK1/2 and Akt, which is reported to increase myelination [ 17 ].…”

FGF/FGFR system in the central nervous system demyelinating disease: Recent progress and implications for multiple sclerosis

“…FGF ligands exercise their functions by binding with their high‐affinity receptor family (FGFR1‐4) and are involved in fundamental physiological processes in adults, including wound repair, angiogenesis, and metabolism. 11 , 12 The roles of FGF/FGFR signaling on essential cellular function control indicates the relevance of this axis in the pathogenesis of MS. 13 , 14 Over the past few years, interventions targeting FGF/FGFR have moderately ameliorated symptoms in animal models, and the conditional deletion of FGFR1 and FGFR2 has shown remarkable therapeutic promise. 15 , 16 Furthermore, several FGF family members are strongly associated with the pathogenesis and course of MS. 17 , 18 , 19 Here, we summarize the latest relevant findings, discuss the function of FGF/FGFR signaling in MS pathogenesis, and describe potential therapeutic advances, providing fresh perspectives on MS therapy.…”