Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females A recent study has shed light on how obesity selectively exacerbates central nervous system (CNS) autoimmunity in females, particularly in the context of multiple sclerosis (MS). The research revealed that obesity intensifies sex-specific interferon signaling, worsening CNS autoimmunity in females. Using a diet-induced obesity (DIO) model in mice with experimental autoimmune encephalomyelitis (EAE), a model for MS, the study showed that obesity induced a pro-inflammatory Th1 serum protein signature in females and worsened CNS autoimmunity by increasing serum interferon (IFN)-α levels and IFN-γ/STAT1 signaling. These findings provide new insights into the impact of obesity on female autoimmune diseases. The study first conducted a proteomic analysis of serum from patients with relapsing-remitting MS (RRMS) and non-MS controls, discovering that RRMS females had higher protein levels regardless of obesity status, with leptin being the only protein increased in obese females. Further analysis pointed to several inflammatory pathways, including S100, Th1, IL-17, and MS signaling pathways, that were increased only in obese females. The study then used a DIO model to demonstrate that obesity worsened EAE severity more prominently in females, with increased demyelination in the spinal cord and greater accumulation of inflammatory CD4+ T cells in the CNS. The research further explored the impact of DIO on MOG-specific Th1 cell responses in female EAE, finding that DIO increased the frequency and number of MOG-specific CD4+ T cells and their IFN-γ production, particularly in females. The study also showed that the increase in Th1 inflammation in DIO female mice was intrinsic to T cells and promoted by ovarian hormones rather than leptin.Finally, the study investigated the impact of DIO on IFN signaling in female CD4+ T cells, finding that HFD treatment enhanced the expression of several IFN-related genes, including ISGs, STAT1, and IL-18Rα. The absence of IFN-α signaling in female CD4+ T cells reversed the enhanced autoimmune response induced by HFD.DOI: 10.1016/j.cmet.2024.07.017
Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation![]()
Gao Y, et al.
A recent study has unraveled the heterogeneity of fibroblasts across various tissues, emphasizing their significant role in cancer progression. By analyzing single-cell sequencing data from 517 human samples, the research identified novel fibroblast subsets, such as HOPX+ and MMP1+, and revealed that the proportions of LRRC15+ fibroblasts and their precursors, PI16+, are closely linked to patient prognosis. The study uncovered distinct fibroblast subtypes with unique immune modulation functions, including immune suppression. Importantly, it showed that the fibroblast composition could categorize patients into subtypes with different clinical outcomes, pointing to potential therapeutic targets in cancer treatment. The comprehensive fibroblast atlas from this research provides insights into the regulatory pathways controlling fibroblast phenotypes, aiding in the understanding of their complexity and the development of effective CAF-targeting cancer therapies.
DOI: 10.1016/j.ccell.2024.04.011.
Editor & Reviewer: Yanwen Wang
