Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases in vitro using primary astrocytes isolated from mice and in vivo using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.

多发性硬化症（MS）是一种影响中枢神经系统（CNS）的炎性自身免疫性疾病，目前尚无任何有效的治疗方法。实验性自身免疫性脑脊髓炎（EAE）通常用作模拟MS临床表现的模型，主要是中枢神经系统脱髓鞘。已知凝血参与炎症和自身免疫的串扰。我们在本文中探讨了凝血级联反应与中枢神经系统免疫疾病之间的相关性体外 使用从小鼠分离的原代星形胶质细胞 体内使用EAE的鼠标模型。我们显示达比加群（dabigatran）是一种临床上的口服抗凝药物，可抑制凝血酶诱导的星形胶质细胞活化，其潜在机制与蛋白酶激活受体1（PAR-1），鞘氨醇-1-磷酸（ S1P）和鞘氨醇激酶（SphKs）。重要的是，达比加群有效地恢复了神经功能，减轻了脊髓的炎症，并防止了由EAE引起的脊髓脱髓鞘。我们认为达比加群是凝血酶的一种特异性抑制剂，它通过限制PAR-1的活化来拮抗星形胶质细胞中凝血酶的作用，进而下调SphK1并破坏S1P受体信号传导。