Social isolation impairs remyelination in mice through modulation of IL‐6

ABSTRACT Recent studies have revealed that social experience affects myelination. These findings have important implications for disorders that feature abnormal myelination, such as multiple sclerosis (MS), as previous studies have shown that psychosocial stress exacerbates the pathobiology of MS. However, most studies have focused on psychosocial stress during the demyelination phase of MSand have not investigated the effects of social experience on remyelination. Thus, the current study sought to determine whether social experience can alter remyelination aftermyelindepletion. Myelininthemousemedialprefrontal cortexwasdepletedwithcuprizone, andthe effects of subsequent social isolation on remyelination were evaluated. Remyelination was severely impaired in socially isolatedmice. Social isolation also increased IL‐6 levels in themedialprefrontal cortex, and administrationof an IL‐6 inhibitor (ND 50 = 0.01–0.03 μg for 0.25 ng/ml IL‐6) ameliorated remyelination impairments. Consistent with this result, IL‐6 administration (ED 50 = 0.02–0.06 ng/ml) disturbed remyelination. In addition, neuron‐oligodendrocyte coculture experiments showed that IL‐6 treatment (ED 50 ≤ 0.02 ng/ml) markedly impeded myelination, which was recoveredwith IL‐6 inhibitor administration (ND 50 = 0.01–0.03 μg for 0.25 ng/ml IL‐6). This study provides the first direct evidence, to our knowledge, that social experience influences remyelination via modulation of IL‐6 expression. These findings indicate that psychosocial stress may disturb remyelination through regulation of IL‐6 expression in patients with such demyelinating diseases that involve remyelination asMS.—Makinodan, M., Ikawa, D., Miyamoto, Y., Yamauchi, J., Yamamuro, K., Yamashita, Y., Toritsuka, M., Kimoto, S., Okumura, K., Yamauchi, T., Fukami, S., Yoshino, H., Wanaka, A., Kishimoto, T. Social isolation impairs remyelination in mice through modulation of IL‐6. FASEB J. 30, 4267–4274 (2016). www.fasebj.org