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Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages
1Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China.
Abstract:
Multiple sclerosis (MS) is a chronic and debilitating autoimmune disease, characterized by chronic inflammatory demyelination in the nervous tissue and subsequent neurological dysfunction. Spermidine, a natural polyamine, has been shown to affect inflammation in some experimental models. We show here that spermidine could alleviate experimental autoimmune encephalomyelitis (EAE), a model for MS, through regulating the infiltration of CD4+ T cells and macrophages in central nervous system. Unexpectedly, we found that spermidine treatment of MOG-specific T cells did not affect their pathogenic potency upon adaptive transfer; however, spermidine diminished the ability of macrophages in activating MOG-specific T cells ex vivo. Depletion of macrophages in diseased mice completely abolished the therapeutic effect of spermidine, indicating a critical role of spermidine-activated macrophages. Mechanistically, spermidine was found to specifically suppress the expression of interleukin-1beta (IL-1β), IL-12 and CD80 while enhance the expression of arginase 1 in macrophages. Interestingly, macrophages from spermidine-treated mice could also reverse EAE progression, while pretreatment of those macrophages with the arginase 1 inhibitor abrogated the therapeutic effect. Therefore, our studies revealed a critical role of macrophages in spermidine-mediated treatment on EAE and provided novel information for better management of MS.
Insights
Spermidine alleviates experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model, by reprogramming macrophages. These spermidine-activated macrophages are key to the therapeutic effect, offering new insights for managing MS.
Area of Science:
- Neuroimmunology
- Immunology
- Molecular Medicine
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease causing neurological dysfunction due to central nervous system inflammation and demyelination.
- Spermidine, a natural polyamine, has demonstrated anti-inflammatory effects in various experimental models.
- Understanding novel therapeutic targets for MS is crucial for improving patient management.
Purpose of the Study:
- To investigate the therapeutic potential of spermidine in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.
- To elucidate the underlying mechanisms of spermidine's action, particularly its effects on immune cells within the central nervous system.
- To identify the specific immune cell populations and molecular pathways involved in spermidine's immunomodulatory effects.
Main Methods:
- Induction of EAE in mice and subsequent treatment with spermidine.
- Assessment of T cell and macrophage infiltration into the central nervous system.
- Ex vivo analysis of MOG-specific T cell activation by macrophages from spermidine-treated mice.
- Macrophage depletion studies and analysis of gene/protein expression (IL-1β, IL-12, CD80, Arginase 1).
- Inhibition of Arginase 1 in macrophages to assess its role in therapeutic efficacy.
Main Results:
- Spermidine treatment alleviated EAE symptoms by modulating CD4+ T cell and macrophage infiltration in the CNS.
- Spermidine did not affect the pathogenic potential of MOG-specific T cells but reduced their activation by macrophages.
- Depletion of macrophages abolished spermidine's therapeutic effect, highlighting their critical role.
- Spermidine suppressed IL-1β, IL-12, and CD80 expression while enhancing arginase 1 in macrophages.
- Macrophages from spermidine-treated mice reversed EAE, an effect abrogated by Arginase 1 inhibition.
Conclusions:
- Macrophages play a pivotal role in the therapeutic effects of spermidine in the EAE model.
- Spermidine exerts its immunomodulatory effects by altering macrophage phenotype and function, notably through Arginase 1.
- These findings offer a novel therapeutic strategy targeting macrophages for managing multiple sclerosis.
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