Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility

Significance Women are much more likely to develop autoimmune diseases, such as systemic lupus erythematous, rheumatoid arthritis, and multiple sclerosis. Sex hormones, including estrogen and testosterone, clearly influence disease susceptibility, but the precise cellular and molecular targets of these hormones have remained unexplained. While most studies have focused on what causes the damaging inflammation in females, there is also much to be learned by studying the factors that confer protection to males. Using a mouse model of multiple sclerosis, a CNS demyelinating disease, we identified a testosterone-driven pathway mediated by mast cell-dependent IL-33 expression that limits the development of a destructive immune response in males. The identification of such pathways has important therapeutic implications.