Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation
Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation
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DOI：
10.1073/pnas.1615413114
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发表时间：
2017-02-21
影响因子：
11.1
通讯作者：
Quintana, Francisco J.
中科院分区：
文献类型：
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作者：
Rothhammer, Veit;Kenison, Jessica E.;Quintana, Francisco J.
多发性硬化症（MS）是一种中枢神经系统自身免疫性炎症性脱髓鞘疾病，由于神经功能缺陷的不可逆积累，导致年轻人残疾。虽然在最初的复发缓解期有有效的疾病调节剂，但这些疗法对继发性进展性MS （SPMS）的疗效有限。因此，对SPMS的疾病机制和潜在治疗方法的识别是一个未满足的临床需求。在这里，我们发现鞘氨醇1-磷酸受体（S1PR）调节剂fingolimod （FTY720）改善了非肥胖糖尿病小鼠的慢性进行性实验性自身免疫性脑脊髓炎，该实验模型类似于SPMS的几个方面，包括中枢神经系统先天免疫反应驱动的神经变性和疾病进展。事实上，小鼠和人类星形胶质细胞中FTY720对S1PR的调节抑制了星形胶质细胞、小胶质细胞和中枢神经系统浸润性促炎单核细胞介导的神经变性促进机制。全基因组研究表明，FTY720抑制与星形胶质细胞促进疾病进展相关的转录程序。控制这些转录模块的分子机制的研究可能为发展进展性MS的治疗策略开辟新的途径。
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.