Abstract
BackgroundADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) plays a vital role in preventing microvascular thrombosis and inflammation. Reduced ADAMTS13 levels in plasma have been detected in multiple sclerosis (MS) patients. In the present study, we have determined the role of ADAMTS13 in the disease progression of MS using a mouse model of experimental autoimmune encephalomyelitis (EAE).MethodsFemale C57BL/6 mice were immunized with MOG35–55 peptide and then treated with ADAMTS13 or vehicle in preventive and therapeutic settings. Mice were analyzed for clinical deficit, white matter demyelination and inflammatory cell infiltration. To explore the underlying mechanism, VWF expression and blood-spinal cord barriers (BSCB) were determined.ResultsPlasma ADAMTS13 activity was suppressed in EAE mice. ADAMTS13-treated EAE mice exhibited an ameliorated disease course, reduced demyelination, and decreased T lymphocyte, neutrophil and monocyte infiltration into the spinal cord. Consistently, ADAMTS13 treatment reduced VWF levels and inhibited BSCB breakdown in the spinal cords of EAE mice. However, leukocytes in the blood and spleen of EAE mice remained unaffected by ADAMTS13 administration.ConclusionOur results demonstrate that ADAMTS13 treatment ameliorates inflammatory responses, demyelination and disease course in EAE mice. Therefore, our study suggests that ADAMTS13 may represent a potential therapeutic strategy for MS patients.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), that is characterized by leukocyte infiltration and myelin damage [1, 2]
Plasma ADAMTS13 activities and von Willebrand factor (VWF) levels in EAE mice To evaluate the role of ADAMTS13 in the development of EAE, the kinetics of plasma ADAMTS13 activity were quantified at different time points
Compared to the naïve group, relative ADAMTS13 activity in EAE mice was obviously reduced at 7 dpi (75.4 ± 6.3%; P < 0.01), remaining low at 14 dpi (73.2 ± 3.3%; P < 0.01)
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), that is characterized by leukocyte infiltration and myelin damage [1, 2]. As an animal model for MS, experimental autoimmune encephalomyelitis (EAE) has been widely used to study the pathophysiology and therapy of MS. It is commonly acknowledged that MS and EAE are mediated by autoreactive T lymphocyte cells that enter the CNS and initiate a chronic autoimmune response [3]. Cells and proteins of the hemostatic system, traditionally studied in thrombotic diseases, clearly play unexpected roles in MS and EAE. Thrombin and fibrinogen [5, 6] proteins were shown to promote CNS inflammation in MS. We have determined the role of ADAMTS13 in the disease progression of MS using a mouse model of experimental autoimmune encephalomyelitis (EAE)
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