Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination

Neuromyelitis optica spectrum disorder, often linked to autoimmune antibodies against aquaporin-4 (AQP4), is a demyelinating disease exhibiting a profound sex bias in female patients. However, the pathophysiological mechanism underlying this clinical manifestation remains to be better understood. In this study, we observe a higher extent of neuroinflammation and demyelination in female mice than in males with the AQP4 antibody-induced disease model. Of importance is that sex hormone depletion in ovariectomized female mice is sufficient to mitigate the disease severity, while estradiol replacement in castrated male mice exacerbates these neuropathological features. We then demonstrate that microglia predominantly express estrogen receptor 1 (Esr1) and that specific deletion of Esr1 inhibits microglia-mediated neuroinflammation and reduces demyelination. Moreover, the administration of fulvestrant, a clinically approved estrogen receptor antagonist, can effectively ameliorate the mouse disease model. These results have elucidated a critical, proinflammatory role of the microglial Esr1 signal in AQP4 antibody-induced neuroinflammation and demyelination with clinical implications.