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Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation
Dylan A Galloway1, John B Williams1, Craig S Moore1
1Division of Bio Medical Sciences Faculty of Medicine Memorial University of Newfoundland St. John's Newfoundland Canada.
Objective:
Dimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). In both the brain and periphery, DMF and its metabolite monomethyl fumarate (MMF) exert anti-inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system (CNS). Direct effects of fumarates on neural progenitor cell (NPC) differentiation toward the oligodendrocyte lineage were also assessed.
Methods:
Primary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF, DMF, or vehicle, astrocytes were stimulated with IL-1β for 24 h; gene and microRNA expression were measured by qPCR. Cytokine production and reactive oxygen species (ROS) generation were also measured. NPCs were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers.
Results:
In both murine and human astrocytes, DMF, but not MMF, significantly reduced secretion of IL-6, CXCL10, and CCL2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced microRNAs -146a and -155 upon stimulation. In NPC cultures, DMF increased the number of O4+ and NG2+ cells.
Interpretation:
These results suggest that DMF, and to a lesser extent MMF, mediates the anti-inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS, DMF may be the active compound mediating the anti-inflammatory effects independent from altered antioxidant gene expression.
Insights
Dimethyl fumarate (DMF) reduces inflammation in astrocytes, a key brain cell, and aids oligodendrocyte development. Monomethyl fumarate (MMF) shows some anti-inflammatory effects but DMF is more potent.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Dimethyl fumarate (DMF) is an approved treatment for relapsing-remitting multiple sclerosis (RRMS).
- DMF and its metabolite monomethyl fumarate (MMF) possess anti-inflammatory and antioxidant properties in the central nervous system (CNS).
- Astrocytes are crucial glial cells in the CNS, playing a significant role in neuroinflammation.
Purpose of the Study:
- To compare the direct effects of DMF and MMF on inflammatory and antioxidant pathways in astrocytes.
- To investigate the impact of DMF and MMF on neural progenitor cell (NPC) differentiation towards oligodendrocytes.
Main Methods:
- Primary astrocyte cultures from murine and human brains were utilized.
- Astrocytes were pretreated with MMF, DMF, or vehicle, then stimulated with IL-1β.
- Gene and microRNA expression, cytokine production, and reactive oxygen species (ROS) generation were measured; NPC differentiation was assessed.
Main Results:
- DMF significantly reduced the secretion of IL-6, CXCL10, and CCL2 in both murine and human astrocytes; MMF had a lesser effect.
- Neither DMF nor MMF significantly increased antioxidant gene expression, but both prevented intracellular ROS production.
- DMF treatment increased the number of O4+ and NG2+ cells in NPC cultures, indicating enhanced oligodendrocyte lineage differentiation.
Conclusions:
- DMF exhibits potent anti-inflammatory effects in astrocytes, with MMF showing a lesser impact.
- The anti-inflammatory actions of DMF in the inflamed CNS appear to be independent of increased antioxidant gene expression.
- DMF promotes oligodendrocyte differentiation, suggesting a potential dual mechanism in neuroprotective therapies.
