Researchers Identify Testosterone-triggered Molecule that Protects Men from MS

A molecule triggered by the male hormone testosterone protects male mice from developing multiple sclerosis, Northwestern Medicine researchers report.

Their discovery may help explain why MS affects more women than men. It could also lead to targeted therapies to protect women against the disease.

The study, “Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility,” appeared in the journal Proceedings of the National Academy of Sciences.

The incidence of MS is three to four times higher in women than in men. Sex also determines the age at which the disease strikes and the course it takes.

Scientists knew these differences stemmed from the much higher testosterone levels in men, but they didn’t know the mechanism that caused the difference.

A research team led by Melissa Brown, a microbiology and immunology professor at Northwestern University’s Feinberg School of Medicine, used mice models of MS to explore the subject.

They found that, in male mice, testosterone could prompt immune cells called mast cells to produce the signaling molecule interleukin-33, or IL-33. The molecule promoted a cascade of cell signals that prevented the activation of inflammation-generating Th17 immune cells. Th17 cells play a key role in the destruction of nerve cells’ protective myelin layer — a hallmark of MS.

To further demonstrate IL-33’s nerve-cell-protective effect, the team blocked the activity of the molecule in male mice. This led to their MS symptoms quickly worsening.

Next the team did tests to see if the molecule could protect females. When they administrated IL-33 to female mice in the early stages of MS, the animals’ symptoms diminished significantly.

In addition, IL-33 reversed the symptoms of female mice with full-blown MS.

“Because testosterone levels are seven to eight times lower in adult women compared to men, we speculate there are insufficient levels in females to activate this protective pathway,” Brown said in a news release. “But we showed we can activate the pathway with the guardian molecule IL-33.”

Brown hopes the discovery leads to “an entirely new kind of therapy for MS.”

“IL-33 therapy has the potential to prevent disease progression by blocking damaging inflammation as well as promoting myelin and neuronal [nerve cell] repair in MS and other” central nervous system diseases, the researchers concluded.