Citation

Multiple sclerosis (MS) is an autoimmune demyelinating disorder developing with higher prevalence in women than men, while accelerated MS progression is evident in men. Mechanisms underlying sexual dimorphism in MS remain unclear. Here, we found that although female and male mice with conditional knockout of p38 in CD11c+ cells initially developed attenuated clinical symptoms of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as has been shown earlier, female mice underwent spontaneous disease progression after day 30 post EAE induction. EAE progression in females was associated with T lymphocyte and macrophage infiltration into the CNS parenchyma. In contrast, male mice with CD11c cell specific p38 deficiency were protected from disease progression as immune cells were trapped within perivascular spaces without entering parenchyma. We identified male-specific p38 signaling in CD11c+CD11b+Iba1+ cells to control immune cell infiltration and progression of autoimmune demyelination. These findings advance our understanding of sex-biased mechanisms in MS relapse and progression and provide new rationale for the development of sex-specific MS therapies.