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.