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Dimethyl fumarate inhibits integrin α4 expression in multiple sclerosis models
Yasuyuki Kihara1, Aran Groves1, Richard R Rivera1
1Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute 10550 N. Torrey Pines Rd., DNC-118, La Jolla, California, 92037.
Annals of Clinical and Translational Neurology
|October 20, 2015
Summary
Dimethyl fumarate treats multiple sclerosis by inhibiting integrin α4 expression on lymphocytes. This occurs through a novel pathway, distinct from the previously known nuclear factor erythroid 2-like 2 activation, offering new insights into its therapeutic effects.
Area of Science:
- Neuroimmunology
- Pharmacology
- Cellular Immunology
Background:
- Dimethyl fumarate (DMF) is an established oral therapy for multiple sclerosis (MS) and psoriasis.
- Its efficacy in MS is often attributed to the activation of nuclear factor erythroid 2-like 2 (Nrf2) pathway.
- A deeper understanding of DMF's molecular targets is crucial for optimizing its therapeutic application.
Purpose of the Study:
- To investigate alternative mechanisms underlying dimethyl fumarate's efficacy in multiple sclerosis.
- To determine if DMF affects integrin α4 expression on lymphocytes.
- To elucidate the relationship between DMF's effect on integrin α4 and Nrf2 activation.
Main Methods:
- Utilized experimental autoimmune encephalomyelitis (EAE) mouse model to study DMF's effects in vivo.
- Assessed integrin α4 expression on circulating lymphocytes in EAE mice.
- Examined the impact of DMF on activated human Jurkat T cells in vitro.
- Compared the observed effects with Nrf2 activation pathways.
Main Results:
- Dimethyl fumarate was found to inhibit the expression of integrin α4 on circulating lymphocytes in the EAE mouse model.
- DMF also reduced integrin α4 expression on activated human Jurkat T cells.
- This inhibition occurred independently of, and was distinct from, the activation of the Nrf2 pathway.
Conclusions:
- Dimethyl fumarate exerts its therapeutic effects in multiple sclerosis through a mechanism involving the inhibition of integrin α4 expression.
- This integrin α4 inhibitory effect is independent of Nrf2 activation, suggesting a novel therapeutic pathway for MS.
- These findings provide a new perspective on the pharmacological action of DMF in treating multiple sclerosis.
