Oligodendrocyte‐specific deletion of FGFR2 ameliorates MOG_35‐55‐induced EAE through ERK and Akt signalling

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte-specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG 35-55induced EAE. Oligodendrocyte-specific knockout of FGFR2 (Fgfr2 ind−/−) was achieved by application of tamoxifen; EAE was induced using the MOG 35-55 peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2 ind−/− mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2 ind−/− mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2 ind−/− mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2 ind−/− mice. Furthermore, expression of IL-1β, TNF-α and CD200 was less in Fgfr2 ind−/− mice than controls. Fgfr2 ind−/− mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF-β expression. These data suggest that cell-specific deletion of FGFR2 in oligodendrocytes has anti-inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS.

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

“…In the cerebellum, Fgfr1 ind−/− mice show increased Akt phosphorylation, which is known to modulate inflammation and TrkB/BDNF expression and enhance myelination in the EAE model. In our previous studies, Fgfr1 ind−/− mice had an increased expression of TrkB and increased phosphorylation of downstream Akt kinase in the spinal cord [15,16]. Akt kinase is a key downstream protein that regulates inflammation [54], and continuous activation of Akt in oligodendrocytes increases myelin synthesis [55].…”

“…Fgfr1 ind−/− and Fgfr2 ind−/− mice showed less motor deficits, reduced inflammation, and demyelination in the spinal cord. Phosphorylation of Akt and ERK was regulated in the spinal cord of both Fgfr1 ind−/− and Fgfr2 ind−/− mice [15,16]. Consequently, data from this disease model of MS suggest that FGFR in oligodendrocytes exert negative effects.…”

“…At day 62 p.i., Fgfr1 ind−/− mice showed less FGF2 and FGF9 expression in the cerebellum. To date, it is unclear why deletion of FGFRs in oligodendrocytes causes a reduction in inflammation in the spinal cord and the cerebellum [15,16]. One may speculate that deletion of FGFRs results in a reduction of FGF2 and FGF9 by regulating the downstream signaling of ERK and Akt, which may reduce inflammation by altering the proinflammatory cytokines.…”

“…Induction and clinical evaluation of EAE was done as previously described [15,16]. Briefly, 8-to 12-week-old female Fgfr1 ind−/− and control mice were injected subcutaneously in the flank with 300 µg of myelin oligodendrocyte glycoprotein peptide (MOG 35-55 ; Charité Hospital, Berlin, Germany) that was emulsified in complete Freund's adjuvant (Sigma, Steinheim, Germany) containing 10 mg of Mycobacterium tuberculosis (Difco, Detroit, MI, USA).…”

“…Analysis of the cerebrospinal fluid (CSF) of patients with relapsing-remitting MS showed higher levels of FGF2 expression than healthy controls and revealed that an increased concentration of FGF2 positively correlates with lesion load of disease activity [14]. Human data indicate the implication of FGF2 in the pathogenesis of MS. We have investigated oligodendrocyte-specific deletion of FGFR in experimental autoimmune encephalomyelitis (EAE) [15,16]. Fgfr1 ind−/− and Fgfr2 ind−/− mice showed less motor deficits, reduced inflammation, and demyelination in the spinal cord.…”