Microglial Estrogen Receptor 1 Signaling Designates the Sex Dimorphism of Neuromyelitis Optica Spectrum Disorder

In this study, we observe a higher extent of neuroinflammation and demyelination in females compared to males in the mouse model of AQP4-antibody-induced NMOSD. In addition, sex hormone depletion in female mice mitigates the disease severity, while estradiol replacement in castrated male mice is sufficient to exaggerate the NMOSD model. We then show that microglia predominantly express the estrogen receptor 1 (ESR1), and its specific deletion in females mimics the disease-ameliorating effect of sex hormone depletion. Moreover, the administration of Fulvestrant, a clinically approved estrogen receptor antagonist, effectively downregulates microglial ESR1 and reduces neuroinflammation and demyelination in female mice.本研究中，我们在AQP4抗体诱导的视神经脊髓炎谱系疾病（NMOSD）小鼠模型中观察到，雌性小鼠的神经炎症与脱髓鞘程度显著高于雄性小鼠。此外，雌性小鼠的性激素耗竭可减轻疾病严重程度；而在去势雄性小鼠中给予雌二醇替代疗法，足以加重NMOSD模型的病情。随后我们发现，小胶质细胞主要表达雌激素受体1（ESR1）；在雌性小鼠中特异性敲除该受体，可模拟性激素耗竭带来的疾病缓解效果。此外，临床获批的雌激素受体拮抗剂氟维司群（Fulvestrant）给药可有效下调小胶质细胞ESR1的表达，并减轻雌性小鼠的神经炎症与脱髓鞘损伤。