Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Abstract

Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2 −/− ) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2 −/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2 −/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4 + cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2 −/− and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.multiple sclerosis | dimethyl fumarate | Nrf2 | EAE | M2 monocytes

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…The clinical benefit of DMF treatment in both Nrf2 2/2 and wild-type mice was associated with a reduction of inflammatory Th1 and Th17 cells, as well as with induction of 366 anti-inflammatory M2 monocytes. At the same time, decreased expression of CD80 and CD86 costimulatory molecules was observed in wild-type, but not in Nrf2 2/2 mice, indicating that at least these effects were NRF2-dependent (Schulze-Topphoff et al, 2016).…”

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

“…DMF can induce apoptosis in circulating immune cells, including lymphocytes and monocytes,8, 9 and exerts anti‐inflammatory effects on both peripheral and CNS‐resident immune cells 3, 10, 11. Recent reports have demonstrated that the Nrf2‐dependent induction of AREs by DMF may be dispensable for neuroprotection, and the influence of DMF on both the innate and adaptive immune response may be the principle mechanism of action 12. Furthermore, it has been demonstrated that the anti‐inflammatory effects of fumarates may be restricted to DMF, with other fumarate metabolites having little influence on inflammation 9, 10, 13, 14.…”

Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

“…S1) (13, 14). DMF succinates kelch-like ECH-associated protein 1 (KEAP1), which activates nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) to produce anti-oxidant and anti-inflammatory effects that nonetheless fail to fully account for the drug’s actions (15). Endogenous fumarate also succinates proteins, with a primary target being the active-site cysteine of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (16).…”