A new study conducted in mice suggests that a specific gene located on the X chromosome could play a significant role in driving brain inflammation.

In female mice, identified by their two X chromosomes, the diabetes drug metformin has shown a potential to counteract inflammation.

Should these initial findings be corroborated by further research, they could illuminate a long-standing medical enigma: why women, possessing two copies of a gene that drives inflammation, are more prone to certain autoimmune diseases, a susceptibility that notably increases after menopause.

Our bodies are equipped with a sophisticated immune system, comprising specialized cells that constantly patrol for and neutralize threats like bacteria and viruses. However, this vital defense mechanism can sometimes tragically misfire, turning against the very body it’s meant to protect.

A prime example of such an autoimmune disorder is Multiple Sclerosis (MS). In MS, the immune system mistakenly targets myelin, the crucial fatty sheath that insulates and safeguards nerve fibers in the brain and spinal cord. This destructive assault on the central nervous system leads to a spectrum of debilitating symptoms, including muscle weakness, impaired mobility, and significant cognitive challenges affecting memory and thought processes.

This disease exhibits a marked gender disparity, affecting women two to three times more frequently than men. Adding to its complex nature, symptoms often intensify and become more debilitating following menopause. While these significant trends have long been observed, scientists only recently uncovered the underlying reasons for this heightened prevalence and post-menopausal worsening.

For decades, Dr. Rhonda Voskuhl, a distinguished neurologist and neuroscientist at UCLA, has dedicated her research to unraveling this persistent enigma. Speaking to Live Science, Voskuhl emphasized that the discernible trend of higher disease rates among women presents “a really valuable clue,” strongly suggesting that an X-linked gene could be the primary driver of this observed difference.

The genetic makeup between sexes differs significantly concerning X chromosomes. While men inherit a single X chromosome from their mothers, women receive one from each parent, resulting in two X chromosomes.

Typically, in women, one of these X chromosomes undergoes a process called “X inactivation,” which silences the majority of its genes. This ensures that only one set of X-linked genes – whether from the maternal or paternal contribution – remains active.

However, a critical exception exists. As researcher Voskuhl explained to Live Science, a handful of genes manage to “escape” this inactivation. Consequently, women exhibit an enhanced level of activity for these specific X-linked genes, effectively receiving a heightened genetic dose compared to men.

A research team led by Voskuhl investigated whether X-linked genes might explain the elevated rates of multiple sclerosis (MS) observed in women. Their study involved analyzing existing data pertaining to human microglia, the brain’s primary immune cells, which had been collected from both male and female individuals diagnosed with MS.

Research has uncovered distinct sex-based differences in microglia: women’s microglia exhibit higher concentrations of KDM6A, a protein encoded by the KDM6A gene located on the X chromosome, compared to those found in men. Furthermore, female cells demonstrated an elevated level of activity in genes associated with immune system functions.

Researchers led by Voskuhl investigated the KDM6A gene’s function within the brain by employing a genetic manipulation technique. They specifically ‘knocked out’ — or deactivated — the gene’s activity in the microglia of laboratory mice. Following this genetic alteration, the team then induced an MS-like condition in the rodents using established scientific protocols.

Female mice engineered to lack a functional KDM6A gene have demonstrated enhanced neurological resilience and motor capabilities, according to new findings. Compared to female mice with a working KDM6A gene, these “knockout” subjects exhibited superior ambulatory function.

Further analysis of their brain tissue revealed compelling differences: the KDM6A-deficient mice displayed significantly less nerve damage and a greater abundance of intact, myelin-covered nerve fibers, which are crucial for efficient neural communication. Additionally, these mice showed a marked decrease in the infiltration of immune T cells, suggesting a less inflammatory environment within their brain tissue.

New research published October 15 in *Science Translational Medicine* revealed that deleting the KDM6A gene showed no discernible effect in male mice. This intriguing finding suggests that the KDM6A gene may specifically contribute to brain inflammation in females. Researchers hypothesize that because females possess two copies of the KDM6A gene, and one copy successfully “escapes” typical genetic silencing, they may consequently experience an elevated presence of the KDM6A protein, potentially driving inflammatory responses.

Researchers sought a pharmaceutical agent that could replicate the therapeutic outcomes observed when the KDM6A gene was absent. Their focus turned to metformin, a drug previously identified for its ability to inhibit the KDM6A enzyme in various cell types. Dr. Voskuhl’s team then investigated whether metformin would exert a similar influence on microglia, the brain’s immune cells.

Their subsequent findings revealed a significant, sex-specific effect: metformin effectively mitigated brain inflammation and improved symptoms in female mice. However, the same treatment demonstrated minimal, if any, impact on male mice.

These findings underscore the critical importance of developing treatments tailored specifically for men and women. This necessity arises from observed variations in KDM6A activity and how the drug metformin affects individuals, depending on their sex. According to Voskuhl, evaluating such therapies solely in men or within a mixed study population could easily obscure their true efficacy in women. Therefore, robust data specifically from female participants must be collected and rigorously analyzed in isolation to accurately assess treatment outcomes.

Dr. Lawrence Steinman, a Stanford University neurologist not involved in the new investigation, lauded the research as profoundly significant. He emphasized its crucial role in pinpointing a key gene that contributes to women’s heightened susceptibility to Multiple Sclerosis. Steinman further stated that the study represents a substantial stride forward in deciphering how the KDM6A gene influences immune activity within the brain and helps maintain microglia — the brain’s primary immune cells — in a subdued state, a sentiment he conveyed to Live Science.

Further rigorous research is imperative to unlock the therapeutic potential of KDM6A inhibition within female microglia. Scientists must conduct comprehensive follow-up studies and clinical trials to precisely identify the most effective strategies for blocking this protein and, critically, to confirm whether such an intervention truly offers tangible clinical benefits.

These findings point to a significant interplay between hormones and inflammation connected to chromosomes. According to Voskuhl, previous research has consistently demonstrated that estrogen typically acts to counteract inflammation throughout the body. This hormonal function is vital for balancing immune activity, offering protection to the female brain against pathogens and excessive inflammatory responses during the reproductive years.

During menopause, the notable decline in estrogen levels results in a diminished protective effect, according to experts.