Distinct chromatin modifications at the Il33 locus in mast cells contribute to sex dimorphic susceptibility to EAE, an autoimmune CNS demyelinating disease

Abstract

Abstract Many autoimmune diseases, including multiple sclerosis (MS), exhibit a striking female bias, but the underlying mechanisms remain poorly understood. Using the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which recapitulates this sex dimorphism, we previously demonstrated that preferential IL-33 expression contributes to male protection. IL-33 expression by mast cells in PLP139–151-immunized males activates type 2 innate lymphoid cells, which in turn drives a non-pathogenic Th2 response to myelin peptide. Testosterone directly activates Il33 in male but not female mast cells, but this male-specific response is also observed with other modes of activation, suggesting there are constraints on the chromatin landscape that limit Il33 expression in females. Here we use chromatin immunoprecipitation (ChIP) and ATAC-seq to examine chromatin modifications at the Il33 locus. At steady state, ChIP assays reveal activating H3K4me3 and H3K9ac histone modifications at the promoter and conserved non-coding sequences within the Il33 gene are most prevalent in male-derived cells, while H3K27me3 repressive marks dominate in females. Increased basal Il33 chromatin accessibility assessed by ATAC-seq is also evident in males. Together, these results indicate that while testosterone can directly stimulate IL-33 production, it also exerts effects on Il33 during development conferring a higher potential for expression in males by altering the chromatin landscape. RNAseq analyses of IgE-activated mast cells revealed a broad range of sex-biased gene expression, indicating that sex hormone influences during development drive epigenetic changes and may be a common mechanism to explain sex dimorphism in immunity.