Tyrosine Kinase Receptors Axl and MerTK Mediate the Beneficial Effect of Electroacupuncture in a Cuprizone-Induced Demyelinating Model

Abstract

Electroacupuncture has been shown to promote remyelination in a demyelinating model of multiple sclerosis (MS) through enhanced microglial clearance of degraded myelin debris. However, the mechanisms involved in this process are yet to be clearly elucidated. It has been revealed that TAM receptor tyrosine kinases (Tyro3, Axl, and MerTK) play pivotal roles in regulating multiple features of microglia, including the phagocytic function and myelin clearance. Therefore, the aim of this study is to further confirm whether electroacupuncture improves functional recovery in this model and to characterise the involvement of the TAM receptor during this process. In addition to naive control mice, a cuprizone-induced demyelinating model was established, and long-term electroacupuncture treatment was administrated. To evaluate the efficiency of functional recovery following demyelination, we performed beam-walking test and rotarod performance test; to objectify the degree of remyelination, we performed transmission electron microscopy and protein quantification of mature oligodendrocyte markers. Oil Red O staining was used to evaluate the deposit of myelin debris. We confirmed that, in cuprizone-treated mice, electroacupuncture significantly ameliorates motor-coordinative dysfunction and counteracts demyelinating processes, with less deposit of myelin debris accumulating in the corpus callosum. Surprisingly, mRNA expression of TAM receptors was significantly upregulated after electroacupuncture treatment, and we further confirmed an increased protein expression of Axl and MerTK after electroacupuncture treatment, indicating their involvement during electroacupuncture treatment. Finally, LDC1267, a selective TAM kinase inhibitor, abolished the therapeutic effect of electroacupuncture on motor-coordinative dysfunction. Overall, our data demonstrate that electroacupuncture could mitigate the progression of demyelination by enhancing the TAM receptor expression to facilitate the clearance of myelin debris. Our results also suggest that electroacupuncture may be a potential curative treatment for MS patients.