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

Recombinant beta interferons-1 (IFNß-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNß-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNß-1a versus the combined application of s.c. IFNß-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1ind-/- mice) in MOG35-55-induced EAE. IFNß-1a (30 mg/kg) was applied s.c. from days 0-7 p.i. of EAE in controls and Fgfr1ind-/- mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNß-1a (400 ng/mL). Application of IFNß-1a over 8 days resulted in less symptoms only at the peak of disease (days 9-11) compared to controls. Application of IFNß-1a in Fgfr1ind-/- mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1ind-/- mice treated with IFNß-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNß-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS.

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

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-1ß, 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.

Oligodendrocyte-specific deletion of FGFR2 ameliorates MOG35-55 -induced EAE through ERK and Akt signalling.

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 MOG35-55 -induced EAE. Oligodendrocyte-specific knockout of FGFR2 (Fgfr2ind-/- ) was achieved by application of tamoxifen; EAE was induced using the MOG35-55 peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2ind-/- 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 Fgfr2ind-/- mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2ind-/- mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2ind-/-  mice. Furthermore, expression of IL-1ß, TNF-α and CD200 was less in Fgfr2ind-/-  mice than controls. Fgfr2ind-/-  mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF-ß 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.

Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune encephalomyelitis through ERK/AKT phosphorylation.

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.

Fgfr2 and Fgfr3 are not required for patterning and maintenance of the midbrain and anterior hindbrain.

The mid-/hindbrain organizer (MHO) is characterized by the expression of a network of genes, which controls the patterning and development of the prospective midbrain and anterior hindbrain. One key molecule acting at the MHO is the fibroblast growth factor (Fgf) 8. Ectopic expression of Fgf8 induces genes that are normally expressed at the mid-/hindbrain boundary followed by the induction of midbrain and anterior hindbrain structures. Inactivation of the Fgf receptor (Fgfr) 1 gene, which was thought to be the primary transducer of the Fgf8 signal at the MHO, in the mid-/hindbrain region, leads to a deletion of dorsal structures of the mid-/hindbrain region, whereas ventral tissues are less severely affected. This suggests that other Fgfrs might be responsible for ventral mid-/hindbrain region development. Here we report the analysis of Fgfr2 conditional knockout mice, lacking the Fgfr2 in the mid-/hindbrain region and of Fgfr3 knockout mice with respect to the mid-/hindbrain region. In both homozygous mouse mutants, patterning of the mid-/hindbrain region is not altered, neuronal populations develop normal and are maintained into adulthood. This analysis shows that the Fgfr2 and the Fgfr3 on their own are dispensable for the development of the mid-/hindbrain region. We suggest functional redundancy of Fgf receptors in the mid-/hindbrain region.

Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA.

Major histocompatibility complex (MHC) class II expression by microglia and astrocytes is critical for CD4+-mediated immune responses within the central nervous system. Here, we demonstrate that the obligate intracellular parasite, Toxoplasma gondii, down-regulates activation-induced MHC class II expression in human-derived glioblastoma cells as well as in primary astrocytes and microglia from cortices of rat fetuses. Down-regulation of MHC class II proteins was predominantly observed in parasite-positive, but not parasite-negative, host cells of T. gondii-infected cell cultures. MHC class II transcript levels induced by IFN-gamma alone or in combination with TNF-alpha were also clearly diminished after parasitic infection. Furthermore, T. gondii dose-dependently down-regulated the transcript levels of the class II transactivator CIITA. These results suggest that T. gondii partially evade CD4+-mediated intracerebral immune responses, a mechanism which may contribute to long-term persistence of the parasite within the CNS.