Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis

OBJECTIVE Dimethyl fumarate (DMF), a therapy for relapsing-remitting multiple sclerosis (RRMS), is implicated as acting on inflammatory and antioxidant responses within both systemic immune and/or central nervous system (CNS) compartments. Orally administered DMF is rapidly metabolized to monomethyl fumarate (MMF). Our aim was to analyze the impact of fumarates on antiinflammatory and antioxidant profiles of human myeloid cells found in the systemic compartment (monocytes) and in the inflamed CNS (blood-derived macrophages and brain-derived microglia). METHODS We analyzed cytokine and antioxidant expression in monocytes from untreated or DMF-treated RRMS patients and controls, and in monocyte-derived macrophages (MDMs) and microglia isolated from adult and fetal human brain tissue. RESULTS Monocytes from multiple sclerosis (MS) patients receiving DMF had reduced expression of the proinflammatory micro-RNA miR-155 and of antioxidant genes HMOX1 and OSGIN1 compared to untreated MS patients; similar changes were observed in patients receiving FTY720 and/or natalizumab. In vitro addition of DMF but not MMF to MDMs and microglia inhibited lipopolysaccharide-induced production of inflammatory cytokines and increased expression of the antioxidant gene HMOX1 in the absence of significant cytotoxicity. INTERPRETATION Our in vivo-based observations that effects of DMF therapy on systemic myeloid cell gene expression are also observed with FTY720 and natalizumab therapy suggests that the effect may be indirect, reflecting reduced overall disease activity. Our in vitro results demonstrate significant effects of DMF but not MMF on inflammation and antioxidant responses by MDMs and microglia, questioning the mechanisms whereby DMF therapy would modulate myeloid cell properties within the CNS.