Dimethyl fumarate does not control immunity via an effect on Nrf2

Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, Cree BA, Sobel RA, Wipke BT, Steinman L, Scannevin RH, Zamvil SS.Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2.
Proc Natl Acad Sci U S A. 2016 pii: 201603907. [Epub ahead of print]

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 anti-inflammatory 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.

How does DMF work? The answer used to be via inhibition of Nrf2 a transcription factor. However the work of Biogen and the Stanford group says this is not how it is working so times to change your slides.

In this study they give Nrf2 knockout mice DMF and it does nothing different from animals that have Nrf2. As MS is a B cell disease these days 🙂 they report that DMF at high dose causes animals to loose MHC class II of their surface so they would not be good antigen presenting cells and hence you should not get EAE.

I have known about this issue for quite a while and so DMF needs a new target, it is mentioned that DMF probably has multiple therapeutic targets. In this regard, MMF is a potent agonist of the hydroxycarboxylic acid receptor 2 (HCAR2) (GPR109A)

Chen et al. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE


However DMF does activate Nrf2 related gene proteins and mayb the work missed a trick by not looking at the animals for long enough to see if the Nrf2-/- recovered worse than the normal mice as this could tell you if it affected nerve loss

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