Microglia-Induced Activation of Noncanonical Wnt Signaling Aggravates Neurodegeneration in Demyelinating Disorders

Abstract

Oligodendrocytes are myelinating cells of the central nervous system. Multiple sclerosis (MS) is a demyelinating disease characterized by both myelin loss and neuronal degeneration. However, the molecular mechanisms underlying neuronal degeneration in demyelinating disorders are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) demyelinating-mouse model of MS, inflammatory microglia produce cytokines, including interleukin-1β (IL-1β). Since microglia and noncanonical Wnt signaling components in neurons, such as the coreceptor Ror2, were observed in the spinal cords of mice with EAE (EAE mice), we postulated that the interplay between activated microglia and spinal neurons under EAE conditions is mediated through noncanonical Wnt signaling. EAE treatment upregulated in vivo expression of noncanonical Wnt signaling components in spinal neurons through microglial activation. In accordance with the neuronal degeneration detected in the EAE spinal cord in vivo, coculture of spinal neurons with microglia or the application of recombinant IL-1β upregulated noncanonical Wnt signaling and induced neuron death, which was suppressed by the inhibition of the Wnt-Ror2 pathway. Ectopic noncanonical Wnt signaling aggravated the demyelinating pathology in another MS mouse model due to Wnt5a-induced neurodegeneration. The linkage between activated microglia and neuronal Wnt-Ror2 signaling may provide a candidate target for therapeutic approaches to demyelinating disorders.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00139-16.

ACKNOWLEDGMENTS

We thank Tetsushi Kagawa (Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University [TMDU], Tokyo, Japan) for the gift of the PCR primers. We also thank Shinji Takada (Okazaki Institute for Integrative Bioscience and National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Japan) and Seiji Hitoshi (Department of Integrative Physiology, Shiga University of Medical Science, Otsu, Japan) for helpful discussions. We thank Rie Taguchi for her technical assistance.

This work was supported by a Grant-in-Aid for Scientific Research (Kakenhi Projects 25117001 “glial assembly”).

We declare that we have no conflict of interest.