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Published on: September 12, 2016
Dimethyl Fumarate Suppresses Demyelination and Axonal Loss through Reduction in Pro-Inflammatory Macrophage-Induced
Sudhir K Yadav1, Naoko Ito1, Devika Soin1,2
1Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Abstract:
Dimethyl fumarate (DMF) is an oral agent for relapsing-remitting multiple sclerosis (RRMS). In this study, we investigated the therapeutic mechanism of DMF using experimental autoimmune encephalomyelitis (EAE). DMF treatment decreased the proliferation of T cells and the production of IL-17A and GM-CSF. DMF treatment also decreased the development and/or infiltration of macrophages in the central nervous system (CNS), and reduced the ratio of iNOS+ pro-inflammatory macrophage versus Ym1+ immunomodulatory macrophages. Furthermore, DMF treatment suppressed the deposition of complement C3 (C3) and development of reactive C3+ astrocytes. The decrease in iNOS+ macrophages, C3+astrocytes, and C3 deposition in the CNS resulted in the reduction in demyelination and axonal loss. This study suggests that the beneficial effects of DMF involve the suppression of iNOS+ pro-inflammatory macrophages, C3+ astrocytes, and deposition of C3 in the CNS.
Insights
Dimethyl fumarate (DMF) reduces T cell activity and central nervous system inflammation in multiple sclerosis models. It suppresses pro-inflammatory macrophages and complement C3, decreasing demyelination and axonal damage.
Area of Science:
- Neuroimmunology
- Pharmacology
Background:
- Dimethyl fumarate (DMF) is an established oral therapy for relapsing-remitting multiple sclerosis (RRMS).
- The precise therapeutic mechanisms of DMF in the central nervous system (CNS) require further elucidation.
Purpose of the Study:
- To investigate the therapeutic mechanism of DMF in a preclinical model of multiple sclerosis.
- To identify key cellular and molecular pathways modulated by DMF treatment in the CNS.
Main Methods:
- Utilized the experimental autoimmune encephalomyelitis (EAE) model to mimic RRMS.
- Assessed T cell proliferation, cytokine production (IL-17A, GM-CSF), macrophage phenotypes (iNOS+, Ym1+), complement C3 deposition, and astrocyte reactivity (C3+) in the CNS.
Main Results:
- DMF treatment significantly decreased T cell proliferation and production of IL-17A and GM-CSF.
- DMF reduced the infiltration of iNOS+ pro-inflammatory macrophages and suppressed C3 deposition and C3+ astrocyte development in the CNS.
- These immunomodulatory effects correlated with reduced demyelination and axonal loss.
Conclusions:
- DMF exerts beneficial effects in EAE by suppressing iNOS+ pro-inflammatory macrophages and complement C3-mediated inflammation in the CNS.
- The findings highlight DMF's role in mitigating neuroinflammation and neurodegeneration, offering insights into its therapeutic action in RRMS.
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