Multiple sclerosis (MS) is a chronic central nervous system demyelinating disease of autoimmune originate. Complement C1q, a complex glycoprotein, mediates a variety of immunoregulatory functions considered important in the prevention of autoimmunity. Although we found that the increased serum C1q level was highly associated with the Fazekas scores and T2 lesion volume of MS patients, the effect and mechanism of C1q on demyelination remains unclear. Cluster analysis and protein array results showed that serum Wnt receptors Frizzled-6 and LRP-6 levels in MS patients were both increased, we proposed that C1q may be involved in demyelination via Wnt signaling. The increased C1q protein levels in the serum and brain tissue were confirmed in a cuprizone (CPZ)-induced demyelination mice model. Moreover, CPZ treatment induced significant increase of LRP-6 and Frizzled-6 protein in mice corpus callosum. LRP-6 extra-cellular domain (LRP-6-ECD) level in the serum and cerebrospinal fluid (CSF) of CPZ mice also significantly increased. Knockdown of the subunit C1s of C1 not only substantially attenuated demyelination, promoted M2 microglia polarization and improved neurological function, but inhibited β-catenin expression and its nuclear translocation in oligodendrocyte progenitor cells (OPCs). In vitro, C1s silence reversed the increased level of LRP-6-ECD in the medium and β-catenin expression in OPCs induced by C1q treatment. Meanwhile, inhibition of C1s also markedly lowered the number of EDU positive OPCs, but enhanced the number of CNPase positive oligodendrocyte and the protein of MBP. The present study indicated that C1q was involved in demyelination in response to CPZ in mice by preventing OPC from differentiating into mature oligodendrocyte via Wnt/β-catenin signaling activation.
Keywords: Complement C1q; Demyelination; Multiple sclerosis; OPC differentiation; Wnt/β-catenin signaling.
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