Obesity Aggravates Female Central Nervous System Autoimmune Diseases Through Sex-Specific Interferon Signaling

In recent years, the rising incidence of central nervous system (CNS) autoimmune diseases in females has garnered widespread attention. Obesity, as a potential environmental risk factor, has gradually become a research hotspot. The latest issue of “Cell Metabolism” published an article entitled “Obesity Intensifies Sex-Specific Interferon Signaling to Selectively Worsen Central Nervous System Autoimmunity in Females,” led by Dr. Brendan Cordeiro and his team. The article reveals how obesity exacerbates the severity of CNS autoimmune diseases in females through sex-specific interferon signaling pathways. This study integrates data from both human and mouse models, providing a profound analysis of the complex interactions between obesity and sex in promoting CNS autoimmune diseases.

Research Background and Objectives

Multiple sclerosis (MS) is an autoimmune disease that attacks the white matter of the CNS, characterized by inflammatory demyelinating lesions driven by autoreactive CD4+ T cells. The risk for females in developing MS is significantly higher than for males, a gender difference that becomes particularly pronounced after puberty. Moreover, the incidence of MS in females has significantly increased over the past decades, a trend consistent with rising obesity rates. Obesity not only affects the risk of developing MS but may also alter T helper cell (Th1 and Th17) immune responses through various mechanisms, promoting the development of CNS autoimmune diseases.

Although the association between obesity and MS has been confirmed, its specific mechanisms remain unclear. To elucidate how obesity promotes CNS autoimmune inflammation through sex-specific mechanisms, this study combined human serum proteomics analysis and mouse model experiments to systematically clarify the immune regulatory processes induced by obesity.

Research Methods

1. Human Serum Proteomics Analysis

The research team compared serum proteomics characteristics among male and female patients with relapsing-remitting MS (RRMS) and healthy control groups, with samples grouped by obesity status (BMI≥30 kg/m² for the obese group, BMI<30 kg/m² for the non-obese group). Using multiplex proteomics analysis, they explored how gender and obesity jointly regulate inflammation-related signaling pathways.

2. Mouse Model Experiments

To further study the effects of obesity on CNS autoimmune diseases, the research team induced obesity in mice using a high-fat diet (HFD) and employed an experimental autoimmune encephalomyelitis (EAE) model to simulate the pathological process of MS. The experiments were divided into the following parts: - Obesity Induction and EAE Model Establishment: Six-week-old C57BL/6J male and female mice were fed either an HFD or normal chow diet (NCD) for four weeks, followed by injection with myelin oligodendrocyte glycoprotein (MOG35–55) and complete Freund’s adjuvant (CFA) to induce EAE. - Immune Cell Analysis: Utilizing flow cytometry to assess the quantity and function of immune cell subsets in the spleen and CNS, including the expression of inflammatory factors by CD4+ T cells. - Gene and Protein Expression Analysis: RNA sequencing and protein expression analysis of CD4+ T cells to study the activation state of interferon signaling pathways. - Sex Hormone Intervention Experiments: Using ovariectomy to study the regulatory effects of estrogen on obesity-related immune responses.

Research Results

1. Gender-Specific Inflammation Characteristics

In human samples, obesity significantly increased the expression levels of inflammation proteins related to Th1 and IL-17, including interferon (IFN) signaling pathways, in the serum of females, with no noticeable changes in males. Proteomics analysis showed that inflammation signaling pathways were significantly upregulated in obese females, including S100 proteins, IL-6, Th1, and MS signaling pathways, and these changes were independent of MS diagnosis status.

2. Obesity Aggravates CNS Inflammation and EAE Severity in Female Mice

In the EAE model, obesity aggravated the disease progression in female mice, manifesting as higher clinical scores, more severe spinal cord demyelination, and stronger infiltration of inflammatory CD4+ T cells in the CNS. In contrast, the effect of exacerbated inflammation was weaker in male mice.

3. Core Role of Interferon Signaling Pathway

The study found that obesity significantly increased the expression of STAT1 and the secretion capacity of IFN-γ in CD4+ T cells of female mice, an effect dependent on type I interferon receptor (IFNAR) signaling. By knocking out IFNAR1 in T cells, the researchers confirmed that type I interferon signaling plays a critical role in obesity-induced CNS inflammation. Moreover, type I interferon signaling upregulated the expression of STAT1 and IL-18 receptors, further enhancing Th1 inflammation.

4. Synergistic Effect of Sex Hormones

Ovariectomy experiments indicated that estrogen amplifies the Th1 inflammatory response induced by obesity by enhancing T cell IFN-γ expression. However, the serum level of type I interferon was not regulated by estrogen.

Significance of the Study

This study reveals the synergistic role of obesity and female gender in promoting CNS autoimmune diseases, providing a new mechanism to explain the gender differences in MS and obesity-related risks. By demonstrating the core role of type I interferon in regulating Th1 inflammation, the study offers important insights for future personalized treatment strategies targeting obese females. Moreover, this work emphasizes the importance of considering gender and obesity factors in MS research and clinical trial design.

Study Highlights and Limitations

Study Highlights

• Mechanistic Insights: Revealed the molecular mechanism by which obesity promotes female Th1 inflammation through type I interferon signaling.
• Gender Differences: Clarified the different effects of obesity on CNS autoimmune diseases in females and males.
• Multi-Model Validation: Integrated experimental results from human data and mouse models, enhancing the study’s credibility.

Study Limitations

• Human Sample Limitations: Primarily studied Caucasian populations, necessitating further verification in diverse races and regions.
• Unknown Tissue Sources: It remains unclear which tissues or cells are responsible for obesity-induced type I interferon production.

Conclusion

Through in-depth mechanistic research, Cordeiro et al. provide new perspectives on understanding the complex relationship between obesity, gender, and CNS autoimmune diseases. This study not only offers crucial insights into the pathogenesis of multiple sclerosis but also brings new hope for intervention strategies in obesity-related autoimmune diseases.