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Dimethyl Fumarate Reduces Microglia Functional Response to Tissue Damage and Favors Brain Iron Homeostasis
Francesca Pagani1, Claudia Testi2, Alfonso Grimaldi2
1Center for Life Nanoscience, Istituto Italiano di Tecnologia, Rome, Italy; Nanotechnology Institute, CNR-Nanotechnology Institute, Sapienza University, Rome, Italy.
Abstract:
Dimethyl fumarate (DMF) is the only available approved drug for first line treatment of multiple sclerosis (MS), a lethal condition impairing central nervous system (CNS). To date, however, little is known of its mechanisms of action. Only recently, it has been suggested that DMF exerts neuroprotective effects acting as an immunomodulator and that it may alter the activation state of microglia cells, crucial in MS pathogenesis. However, DMF effects on microglia functions are still not well determined. Here, we examine the effects of DMF treatment on microglia functional activities, as phenotype, morphology, processes motility and rearrangement, migration, ATP response and iron uptake in mouse primary microglia culture and acute hippocampal slices. We found that DMF treatment reduces microglia motility, downregulating functional response to ATP, increases ferritin uptake and pushes microglia towards an anti-inflammatory phenotype, thus reducing its proinflammatory reactivity in response to tissue damage. These results highlight the effects of this compound on microglia functions and provide new insights on the mechanism of action of DMF in MS treatment.
Insights
Dimethyl fumarate (DMF) is a key treatment for multiple sclerosis (MS). This study reveals DMF reduces microglia inflammation and alters their function, offering new insights into its neuroprotective mechanisms in MS.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Dimethyl fumarate (DMF) is the primary treatment for multiple sclerosis (MS), a debilitating central nervous system (CNS) disease.
- The precise mechanisms of DMF's neuroprotective action, particularly its effects on microglia, remain incompletely understood.
- Microglia play a critical role in MS pathogenesis, and modulating their activity is a key therapeutic strategy.
Purpose of the Study:
- To investigate the impact of Dimethyl fumarate (DMF) on various functional activities of microglia.
- To elucidate how DMF influences microglia phenotype, motility, migration, and inflammatory responses relevant to MS.
Main Methods:
- Primary mouse microglia cultures and acute hippocampal slices were treated with DMF.
- Microglia functional activities including phenotype, morphology, motility, migration, ATP response, and iron uptake were assessed.
Main Results:
- DMF treatment decreased microglia motility and their response to ATP.
- DMF increased ferritin uptake and promoted an anti-inflammatory microglia phenotype.
- These changes suggest DMF reduces pro-inflammatory microglia reactivity.
Conclusions:
- Dimethyl fumarate (DMF) modulates key microglia functions, including reducing inflammatory responses and altering iron metabolism.
- These findings provide novel insights into the therapeutic mechanisms of DMF in treating multiple sclerosis (MS).
