Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females

Obesity has been implicated in the rise of autoimmunity in women. We report that obesity induces a serum protein signature that is associated with T helper 1 (Th1), interleukin (IL)-17, and multiple sclerosis (MS) signaling pathways selectively in human females. Females, but not male mice, subjected to diet-induced overweightness/obesity (DIO) exhibited upregulated Th1/IL-17 inflammation in the central nervous system during experimental autoimmune encephalomyelitis, a model of MS. This was associated with worsened disability and a heightened expansion of myelin-specific Th1 cells in the peripheral lymphoid organs. Moreover, at steady state, DIO increased serum levels of interferon (IFN)-α and potentiated STAT1 expression and IFN-γ production by naive CD4+ T cells uniquely in female mice. This T cell phenotype was driven by increased adiposity and was prevented by the removal of ovaries or knockdown of the type I IFN receptor in T cells. Our findings offer a mechanistic explanation of how obesity enhances autoimmunity. [Display omitted] •In women, obesity induces a pro-inflammatory Th1 serum protein signature•In female mice, obesity promotes Th1 inflammation and worsens CNS autoimmunity in EAE•Obesity increases serum IFN-α level and IFN-γ/STAT1 signaling in female CD4+ T cells•Obesity exacerbates EAE in females through type I IFN signaling in T cells Mechanisms by which obesity and female sex synergize to facilitate CNS autoimmunity remain elusive. Cordeiro and Ahn et al. reveal a female-specific effect of obesity in triggering Th1 inflammatory signatures in humans and augmenting IFN-γ/STAT1 signaling in mouse CD4+ T cells through type I IFN signaling, thereby exacerbating CNS autoimmunity.