Spleen-brain axis regulates myelin integrity via TGF-β1 signaling in cuprizone-induced demyelination and...

Demyelination and impaired remyelination are hallmark features of many neurodegenerative and psychiatric disorders. Although central mechanisms have been widely investigated, the contribution of peripheral immune organs such as the spleen remains poorly understood. In this study, we examined the role of the spleen and transforming growth factor-β1 (TGF-β1) in cuprizone (CPZ)-induced demyelination and remyelination in mice. Splenectomy performed before CPZ exposure significantly worsened demyelination in the corpus callosum, as indicated by reduced myelinated area and myelin basic protein (MBP) intensity. Likewise, splenectomy immediately after CPZ withdrawal markedly impaired remyelination during the recovery phase. Immunohistochemical analysis showed that splenectomy reduced TGF-β1 expression in the corpus callosum at both 2 and 7 weeks after surgery. Moreover, systemic administration of a neutralizing anti-TGF-β1 antibody during either the demyelination or remyelination phase reproduced the effects of splenectomy, resulting in greater myelin loss or reduced myelin repair, respectively. Antibody treatment significantly decreased TGF-β1 levels in both brain and plasma, which were positively correlated with the degree of myelination. Together, these findings reveal a previously unrecognized role of the spleen in preserving myelin integrity and facilitating repair through TGF-β1 signaling. They further suggest that the spleen-brain axis contributes to myelin homeostasis and that peripheral TGF-β1 may represent a potential biomarker and therapeutic target for demyelinating disorders.