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<sup>+</sup> 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.
Authors
- Natalie Stickle (ORCID: https://orcid.org/0000-0003-4822-0347)
- Daniel A. Winer (ORCID: https://orcid.org/0000-0002-8702-0957)
- Joel M. Guthridge (ORCID: https://orcid.org/0000-0002-9308-237X)
- Shannon E. Dunn (ORCID: https://orcid.org/0000-0002-6878-0563)
- Brendan Cordeiro (ORCID: https://orcid.org/0000-0001-5677-0686)
- David G. Brooks (ORCID: https://orcid.org/0000-0001-7763-8764)
- Saurabh Gawde (ORCID: https://orcid.org/0000-0002-8644-2277)
- Xavier S. Revelo (ORCID: https://orcid.org/0000-0002-2754-509X)
- Gabriel Pardo (ORCID: https://orcid.org/0000-0002-2207-3708)
- Nuria Álvarez‐Sánchez (ORCID: https://orcid.org/0000-0002-1313-0440)
- Jeeyoon Jennifer Ahn (ORCID: https://orcid.org/0000-0002-1431-6351)
- Kaylea Massey
- Carmen C. Ucciferri (ORCID: https://orcid.org/0000-0002-2883-5953)
- Robert C. Axtell (ORCID: https://orcid.org/0000-0002-1435-4753)
Institutions
- St. Michael's Hospital (CA)
- University of Minnesota (US)
- University Health Network (CA)
- University of Toronto (CA)
- Women's College Hospital (CA)
- Princess Margaret Cancer Centre (CA)
- Oklahoma Medical Research Foundation (US)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1016/j.cmet.2024.07.017
- Citations
- 16
- Primary Topic
- Atherosclerosis and Cardiovascular Diseases
- Type
- article
- Field-Weighted Citation Impact
- 3.85
Funders
- Multiple Sclerosis Society of Canada
- National Institutes of Health
- IBM Canada
- Canadian Institutes of Health Research