Experimental Neurology, Department of Neurology, University of Giessen, Klinikstrasse 33, 35385 Giessen, Germany.
Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstrasse 6, 97080 Würzburg, Germany.
Int J Mol Sci. 2022 Oct 12;23(20):12183. doi: 10.3390/ijms232012183.
Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNβ-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. IFNβ-1a versus the combined application of s.c. IFNβ-1a and oligodendrocyte-specific deletion of FGFR1 ( mice) in MOG-induced EAE. IFNβ-1a (30 mg/kg) was applied s.c. from days 0-7 p.i. of EAE in controls and 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 IFNβ-1a (400 ng/mL). Application of IFNβ-1a over 8 days resulted in less symptoms only at the peak of disease (days 9-11) compared to controls. Application of IFNβ-1a in mice resulted in less symptoms primarily in the chronic phase of EAE. mice treated with IFNβ-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNβ-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.
重组β干扰素-1（IFNβ-1）被用作复发型多发性硬化症（MS）患者的一线治疗药物，MS 是一种中枢神经系统的慢性炎症性和神经退行性疾病。IFNβ-1a/b 对预防复发和减缓疾病进展有一定疗效。成纤维细胞生长因子（FGFs）及其受体（FGFRs）在 MS 及其 EAE 模型的病理中发挥关键作用。为了研究皮下注射 IFNβ-1a 与皮下注射 IFNβ-1a 联合少突胶质细胞特异性 FGFR1 缺失（ 小鼠）在 MOG 诱导的 EAE 中的短期治疗效果。IFNβ-1a（30mg/kg）在 EAE 感染后 0-7 天（p.i.）经皮下注射应用于对照组和 小鼠。通过 Western blot 分析 MS/EAE 中与炎症/退变相关的 IFNβ-1a 脊髓内信号蛋白。此外，用 PD166866 抑制 Oli-neu 少突胶质细胞中的 FGFR1，并以 IFNβ-1a（400ng/ml）处理。与对照组相比，IFNβ-1a 应用 8 天仅在疾病高峰期（第 9-11 天）症状减轻。IFNβ-1a 在 小鼠中的应用主要在 EAE 的慢性期减轻症状。用 IFNβ-1a 处理的 小鼠表现出 pERK 和 BDNF 的表达增加。在 Oli-neu 少突胶质细胞中，PD166866 和 IFNβ-1a 联合处理也显示出 pERK 和 BDNF/TrkB 的表达增加。这些数据表明，EAE 慢性期的有益作用以及与 ERK 和 BDNF 表达相关的信号分子的作用是由 FGFR1 的调节引起的，而不是由干扰素-β-1a 引起的。FGFR 可能是 MS 治疗的潜在靶点。
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