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

Recombinant beta interferons-1 (IFN beta-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFN beta-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. IFN beta-1a versus the combined application of s.c. IFN beta-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1(ind)(-/-) mice) in MOG(35-55)-induced EAE. IFN beta-1a (30 mg/kg) was applied s.c. from days 0-7 p.i. of EAE in controls and Fgfr1(ind)(-/-) 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 IFN beta-1a (400 ng/mL). Application of IFN beta-1a over 8 days resulted in less symptoms only at the peak of disease (days 9-11) compared to controls. Application of IFN beta-1a in Fgfr1(ind)(-/-) mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1(ind)(-/-) mice treated with IFN beta-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFN beta-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.

Automated summary

This study found that short-term treatment with IFN beta-1a can alleviate symptoms during the peak of disease in multiple sclerosis, while the combined application of IFN beta-1a and specific deletion of FGFR1 can reduce symptoms in the chronic phase. These beneficial effects may be caused by the modulation of FGFR1 rather than interferon beta-1a.