Thrombomodulin-dependent protein C activation is required for mitochondrial function and myelination in the central nervous system.

SummaryBackground Studies with human samples and in rodents established a function of coagulation proteases in neuro-inflammatory demyelinating diseases, e.g. in multiple sclerosis (MS) and experimental autoimmune encephalitis (EAE). Surprisingly, approaches to increase aPC plasma levels as well as antibody mediated inhibition of PC/aPC ameliorated EAE in mice. Hence, the role of aPC generation in demyelinating diseases and potential mechanisms involved remain controversial. Furthermore, it is not known whether loss of aPC has pathological consequences at baseline, e.g. in the absence of disease. Objective To explore the role of thrombomodulin(TM)-dependent aPC generation at baseline and in immunological and non-immunological demyelinating disease models. Methods Myelination and ROS generation were evaluated in mice with genetically reduced TM-mediated protein C activation (TMPro/Pro) and in wild type mice under control conditions or following induction of EAE. Non-immunological demyelination was analysed in the cuprizone-diet model. Results Impaired TM-dependent aPC generation disturbs myelination and mitochondrial function already at baseline. This basal phenotype is linked with increased mitochondrial ROS and aggravates EAE. Reducing mitochondrial ROS (p66Shc deficiency), restoring aPC plasma levels, or injecting soluble TM (solulin) ameliorate EAE in TMPro/Pro mice. Soluble TM additionally conveyed protection in wt-EAE mice. Furthermore, soluble TM dampened demyelination in the cuprizone-diet model, demonstrating that its myelin-protective effect is partially independent of an immune-driven process. Conclusion These results uncover a novel physiological function of TM-dependent aPC generation within the CNS. Loss of TM-dependent aPC generation causes a neurological defect in healthy mice and aggravates EAE, which can be therapeutically corrected. This article is protected by copyright. All rights reserved.