Abstract
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.
Highlights
Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) mostly occurring in young and middle-aged people aged 20–40 years (Ransohoff et al, 2015)
The protein and gene expression of S1P were both significantly increased by 6 h with LPS or thrombin stimulation, but the use of dabigatran etexilate (Dab) counteracted the effect of the stimulants by decreasing the protein and gene expression of S1P
These results signify that LPS- and thrombin-induced inflammation and S1P activation in astrocytes were attenuated by Dab, which showed similar effects as those of protease-activated receptor-1 (PAR-1)-inh
Summary
Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) mostly occurring in young and middle-aged people aged 20–40 years (Ransohoff et al, 2015). To study the pathogenesis of MS, the experimental autoimmune encephalomyelitis (EAE) model has been developed to mimic the phenomenon of demyelination in the CNS (Rivers et al, 1933) In this model, autoimmunity-prone female C57BL6 mice are induced by myelin oligodendrocyte glycoprotein (MOG) to trigger autoimmune responses (Kataoka et al, 2005). Autoimmunity-prone female C57BL6 mice are induced by myelin oligodendrocyte glycoprotein (MOG) to trigger autoimmune responses (Kataoka et al, 2005) This in turn causes pathological demyelination and activation of cytotoxic T lymphocytes to attack the myelin sheath of the CNS, simulating the clinical manifestation and symptoms of MS (Jagessar et al, 2015; Peschl et al, 2017)
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