‘Guardian’ Immune Cells of Brain Respond Differently by Sex, Study of Male and Female Mice Reports

Gender differences are evident in immune system cells of the brain called microglia, a study in male and female mice reports, suggesting these cells’ sex-specific features may be important to treating people with  multiple sclerosis (MS) and other neurological diseases.

The study “Transcriptional and Translational Differences of Microglia from Male and Female Brains” was published in the journal Cell Reports.

Microglia act as the first and primary form of active defense in the central nervous system, which comprises the brain and spinal cord. They regularly survey their surroundings for infectious agents, damaged cells or other injuries, helping to remove these threats and promote tissue healing.

Microglia are extremely sensitive cells capable of detecting even small changes in their environment.

Researchers at the Max Delbrück Center for Molecular Medicine (MDC) and Charité – Universitätsmedizin Berlin, both in Berlin, confirmed earlier research suggesting that microglia works very differently in males and females in a study of these immune cells in mouse models.

Neuroinflammation, their study notes, is common to many neurological diseases, “and thus microglia, as the brain’s immunocompetent cells, have come into focus in sex-specific studies. Here, we show differences in the structure, function, and transcriptomic and proteomic profiles in microglia freshly isolated from male and female mouse brains.”

The scientists analyzed the gene and protein signatures (transcriptomic and proteomics profiles) of brain slices and isolated microglia of male and female mice, and observed that their numbers, their shape and the proteins they express (produce, essentially) differ between sexes.

Specifically, microglia cells are larger and more numerous in the brains of male mice than their female counterparts. Several of the genes that were active and the composition of proteins, key in determining a cell’s function, also distinguished males from females. 

“We identified more than 1,000 genes and 300 to 400 proteins that are regulated differently according to sex,”  Susanne Wolf, PhD, a researcher at the Cellular Neurosciences Lab at MDC and senior author of the study, said in a press release.

Importantly, differences were reflected in cell behavior. “The microglia of male animals seem to be permanently at attention, ready to strike and keep order,” Wolf said.

Male microglia are potentially capable of a stronger stimulation of immune T-cells during inflammation, and are able to respond more robustly to ATP, a signaling molecule of brain injury.

Female microglia seem to be better at surviving insults.

“In the female cells, proteins and genes responsible for protecting cells, such as DNA repair genes, are more active,” Wolf said. This suggests that, as a consequence of their higher state of alertness, male microglia may be worse at protecting themselves against environmental damage because they react more quickly to trigger their own suicide program.

The findings add to the importance of accounting for sex differences when conducting research into neurological diseases and looking for ways to better treat them.

“Our study clearly confirms this hunch: the brain immune cells of both sexes act very differently,” said Dilansu Guneykaya, a PhD student at MDC and the study’s first author, adding these differences might also factor in psychiatric disorders.

Sex-specific differences might also be a reason multiple sclerosis is about twice as prevalent in women than in men. Gender differences are also seen in other neurological disorders, like autism, which is about four times more commonly diagnosed in boys than girls.

Clinical studies testing medications for neurological disorders must be aware that the brains of men and woman could respond very differently to the same agent, Wolf emphasized. 

“The differences are there, but are not yet sufficiently taken into account when treating patients,” she concluded.