Estrogen may drive brain inflammation in NMOSD: Mouse study
Depletion of sex hormone lessened nerve cell damage in female mice
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Depletion of sex hormone production by surgical removal of the ovaries significantly lessened activation of microglia — the brain’s immune cells —as well as neuroinflammation and nerve cell damage in female mice with induced neuromyelitis optica spectrum disorder (NMOSD)-like disease, a study shows.
Similar effects were found in castrated male mice with NMOSD-like disease that were treated with estrogen, a sex hormone mainly produced by the ovaries that regulates the female reproductive system.
Further tests pinpointed estrogen signaling, via the estrogen receptor 1 (ESR1) protein, in microglia as a driver of neuroinflammation and nerve damage in the mouse model of NMOSD, a disease that more commonly affects women.
“Our current study elucidated that estrogen signaling via Esr1 promotes microglial responses in the mouse model of [NMOSD], providing a potential explanation for the [sex-specific differences] of NMOSD,” researchers wrote.
The study, “Microglial estrogen receptor 1 signal designates sexual dimorphism of AQP4 antibody-induced neuroinflammation and demyelination,” was published in Cell Reports.
NMOSD affects women far more often than men
NMOSD is a rare disease marked by inflammation of the spinal cord and optic nerves, which relay signals between the eyes and the brain. This ultimately damages myelin, the protective coating around nerve fibers that helps signals travel through the nervous system.
Although the exact causes of nerve damage in NMOSD are not fully understood, self-reactive antibodies against the AQP4 protein and activation of microglia are thought to play a role.
Microglia, the immune cells that reside in the brain, spinal cord, and optic nerves, help coordinate immune responses, fight infections in the brain, and repair injury. However, they can also contribute to myelin loss in NMOSD.
One notable feature of NMOSD is that it affects women far more often than men. Studies suggest that for every man diagnosed with the disease, between five and nine women are affected. It’s thought that female sex hormones, such as estrogen, may influence the immune system, but the exact reasons for sex differences are still not fully understood.
Female mice showed higher levels of inflammatory markers
To investigate further, researchers in China examined a mouse model of induced NMOSD that involves injecting mice with anti-AQP4 antibodies and other immune proteins, resulting in rapid brain inflammation and clear myelin damage.
First, they found that female mice with NMOSD-like disease showed stronger microglial activation and greater neuroinflammation than male mice after receiving the same injections.
In female mice, microglia multiplied more and showed higher levels of inflammatory markers, with greater myelin loss and more damage to oligodendrocytes, the cells that produce myelin. In contrast, male mice showed milder disease. Their microglia were less active, and they experienced less myelin damage and fewer oligodendrocyte losses.
To confirm microglial involvement in NMOSD-related nerve cell damage, a gene was deleted in the animals’ microglia to prevent them from mounting a strong inflammatory response. Following anti-AQP4 antibody exposure, microglial growth and activation were markedly reduced, resulting in significantly less myelin damage, indicating that microglia were a major driver of the disease in this model.
Female mice without ovaries showed reduced microglia activity
To investigate why female mice experienced more severe disease, the team focused on estrogen signaling, a biological pathway influenced by female sex hormones.
First, the scientists removed the ovaries of female mice, which greatly reduced estrogen levels. After exposure to anti-AQP4 antibodies, the brain’s inflammatory response in these female mice was much weaker than in those with normal hormone levels. Microglia showed reduced growth and activity, resulting in less myelin loss.
The team then castrated male mice to remove their natural male hormones and treated them with estradiol, a major form of estrogen typically found at higher levels in females. After exposure to anti-AQP4 antibodies, these mice showed increased microglial growth, higher levels of inflammatory proteins, and more severe myelin damage than mice with unaltered hormone levels.
Next, researchers genetically modified mice to specifically lack, in microglia, the gene that codes for the estrogen receptor 1 protein. When the disease was induced, the microglia didn’t respond as strongly as those in normal mice, with reduced growth, fewer inflammatory signals, and less myelin damage. Removing the gene that codes for the estrogen receptor 2, did not affect inflammation, supporting that ESR1 is the key estrogen receptor involved in this process.
Lastly, to explore whether blocking the ESR1 could serve as a treatment strategy, the team assessed the impact of fulvestrant, a medication that blocks estrogen receptors and is approved to treat certain types of advanced breast cancer.
Female mice exposed to anti-AQP4 antibodies and treated with fulvestrant showed a much weaker inflammatory response in the brain, marked by less active microglia and less myelin loss. Further experiments confirmed that fulvestrant’s protective effect is mediated by direct reduction of microglial activity.
“These results have elucidated a critical, proinflammatory role of the microglial Esr1 signal in AQP4 antibody-induced neuroinflammation and demyelination with clinical implications,” the researchers wrote.
