Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Abstract

ObjectiveDimethyl 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.MethodsPrimary 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.ResultsIn 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.InterpretationThese 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.

The Role of Astrocytes in Multiple Sclerosis

“…This effect might ameliorate astrocytic damage in active lesions, including the retraction of perivascular astrocyte end feet along basal lamina ( 16 ), to reduce leakage across the BBB and the cortical surface ( 163 ). DMF also inhibits secretion of pro-inflammatory cytokines and chemokines by astrocytes and microglial cells, independent of changes in antioxidant gene expression ( 164 ). Therefore, in addition to its effect on the peripheral immune system, DMF has a direct impact on the CNS that involves protective and anti-inflammatory effects on astrocytes.…”

Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization

“…The molecular masses of the proteins are indicated on the left-hand side. entiation of oligodendrocyte precursor cells (OPC) to oligodendrocytes, as evidenced by increased expression of O4 (47). Recently, Zuchero et al described that early oligodendrocyte differentiation from OPCs is accompanied by the extension of processes containing ordered arrays of actin filaments, requiring polymerized actin and low cofilin activity (48).…”

Effect of dimethyl fumarate on heme oxygenase-1 expression in experimental allergic encephalomyelitis in rats

“…On the other hand, data obtained from murine and human astrocytes treated with DMF, and activated with IL-1β, show no significant difference in HO-1 and NQO-1 expression at the mRNA level. Some authors have suggested that the effect of DMF may be cell specific or even Nrf2 independent [10]. Animal studies by Linker et al [23], showing Nrf2 activation in the chronic phase of EAE induced in mice treated with DMF, revealed increased Nrf2 expression in neurons, oligodendrocytes, and astrocytes, but not in microglia or in T cells, in the spinal cords collected from the animals on the 74 th DPI.…”