Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females
Brendan Cordeiro, Jeeyoon Jennifer Ahn, Saurabh Gawde, Carmen C. Ucciferri, Nuria Álvarez‐Sánchez, Xavier S. Revelo, Natalie Stickle, Kaylea Massey, David G. Brooks, Joel M. Guthridge, Gabriel Pardo, Daniel A. Winer, Robert C. Axtell, Shannon E. Dunn
Abstract
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.