Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA.
Department of Regenerative Medicine, Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH, 44115-2634, USA.
J Neuroinflammation. 2018 Apr 24;15(1):121. doi: 10.1186/s12974-018-1164-y.
Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination. This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Using a mouse model of progressive MS, this study evaluates the effects of sustained TNF on oligodendrocyte (OLG) apoptosis and OLG precursor cell (OPC) differentiation.
Induction of experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a dominant-negative interferon-γ receptor under the human glial fibrillary acidic protein promoter (GFAPγR1Δ) causes severe non-remitting disease associated with sustained TNF. Therapeutic effects in GFAPγR1Δ mice treated with anti-TNF compared to control antibody during acute EAE were evaluated by assessing demyelinating lesion size, remyelination, OLG apoptosis, and OPC differentiation.
More severe and enlarged demyelinating lesions in GFAPγR1Δ compared to wild-type (WT) mice were associated with increased OLG apoptosis and reduced differentiated CC1Olig2 OLG within lesions, as well as impaired upregulation of TNF receptor-2, suggesting impaired OPC differentiation. TNF blockade during acute EAE in GFAPγR1Δ both limited OLG apoptosis and enhanced OPC differentiation consistent with reduced lesion size and clinical recovery. TNF neutralization further limited increasing endothelin-1 (ET-1) expression in astrocytes and myeloid cells noted in lesions during disease progression in GFAPγR1Δ mice, supporting inhibitory effects of ET-1 on OPC maturation.
Our data implicate that IFNγ signaling to astrocytes is essential to limit a detrimental positive feedback loop of TNF and ET-1 production, which increases OLG apoptosis and impairs OPC differentiation. Interference of this cycle by TNF blockade promotes repair independent of TNFR2 and supports selective TNF targeting to mitigate progressive forms of MS.
肿瘤坏死因子 (TNF) 与多种神经退行性疾病有关，包括多发性硬化症 (MS)。尽管 TNF 靶向治疗在 MS 中基本无效，但最近的临床前数据表明，选择性可溶性 TNF 抑制可促进髓鞘再生。这重新引起了人们对脱髓鞘疾病中 TNF 信号调节的兴趣，尤其是在 MS 进行性疾病的治疗选择有限的情况下。本研究使用进展性 MS 的小鼠模型，评估了持续 TNF 对少突胶质细胞 (OLG) 凋亡和 OLG 前体细胞 (OPC) 分化的影响。
在人胶质纤维酸性蛋白启动子 (GFAPγR1Δ) 下表达显性失活干扰素-γ 受体的转基因小鼠中诱导实验性自身免疫性脑脊髓炎 (EAE)，导致与持续 TNF 相关的严重非缓解疾病。在急性 EAE 期间，用抗 TNF 治疗与对照抗体治疗 GFAPγR1Δ 小鼠的治疗效果通过评估脱髓鞘病变大小、髓鞘再生、OLG 凋亡和 OPC 分化来评估。
与野生型 (WT) 小鼠相比，GFAPγR1Δ 小鼠的脱髓鞘病变更严重且更大，与 OLG 凋亡增加以及病变中分化的 CC1Olig2 OLG 减少有关，同时 TNF 受体-2 的上调受损，提示 OPC 分化受损。在 GFAPγR1Δ 中的急性 EAE 期间阻断 TNF 不仅限制了 OLG 凋亡，而且增强了 OPC 分化，与病变缩小和临床恢复一致。TNF 中和进一步限制了在疾病进展过程中 GFAPγR1Δ 小鼠病变中观察到的星形胶质细胞和髓样细胞中内皮素-1 (ET-1) 表达的增加，支持 ET-1 对 OPC 成熟的抑制作用。
我们的数据表明，IFNγ 信号转导至星形胶质细胞对于限制 TNF 和 ET-1 产生的有害正反馈循环至关重要，该循环增加 OLG 凋亡并损害 OPC 分化。通过 TNF 阻断干扰此循环可促进独立于 TNFR2 的修复，并支持选择性 TNF 靶向以减轻 MS 的进行性形式。
