U1195 Inserm, Paris-Saclay University, Kremlin-Bicêtre, France.
UMR996 Inserm, Paris-Saclay University, Clamart, France.
Nat Commun. 2023 Mar 22;14(1):1592. doi: 10.1038/s41467-023-36846-w.
Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.
雄激素具有神经保护、抗炎和促进髓鞘再生的特性，这在脱髓鞘雄性小鼠和多发性硬化症男性患者中得到了很好的证实。然而，雄激素受体 (AR) 介导的雄激素作用在产生低雄激素水平的女性中研究甚少。在这里，我们发现在脱髓鞘病变的女性小鼠和多发性硬化症女性中，小胶质细胞 AR 的表达占主导地位，而在脱髓鞘病变的雄性动物和多发性硬化症男性中几乎检测不到 AR 的表达。在雌性小鼠中，雄激素和雌激素以协同方式发挥作用，而雄激素则促使小胶质细胞向再生方向反应。脱髓鞘小鼠脊髓的转录组比较表明，无论性别如何，雄激素都上调与神经元功能完整性和髓鞘生成相关的基因。根据性别不同，雄激素在女性中下调与免疫系统相关的基因，在男性中下调与脂质分解代谢相关的基因。因此，雄激素是女性髓鞘再生所必需的，脱髓鞘疾病的治疗方法需要考虑到男女之间的差异。
