title: 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.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Program in Immunology, University of California, San Francisco, CA 94143;
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze-Topphoff
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Program in Immunology, University of California, San Francisco, CA 94143;
authors.forename: Michel
authors.initials: M
authors.lastname: Varrin-Doyer
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Program in Immunology, University of California, San Francisco, CA 94143;
authors.forename: Kara
authors.initials: K
authors.lastname: Pekarek
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Program in Immunology, University of California, San Francisco, CA 94143;
authors.forename: Collin M
authors.initials: CM
authors.lastname: Spencer
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Program in Immunology, University of California, San Francisco, CA 94143;
authors.forename: Aparna
authors.initials: A
authors.lastname: Shetty
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Program in Immunology, University of California, San Francisco, CA 94143;
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sagan
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143;
authors.forename: Bruce A C
authors.initials: BA
authors.lastname: Cree
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305;
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: Biogen, Inc., Cambridge, MA 02142;
authors.forename: Brian T
authors.initials: BT
authors.lastname: Wipke
authors.affiliation: Department of Neurology, Stanford University, Stanford, CA 94305 zamvil@ucsf.neuroimmunol.org steinman@stanford.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Biogen, Inc., Cambridge, MA 02142;
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143; Program in Immunology, University of California, San Francisco, CA 94143; zamvil@ucsf.neuroimmunol.org steinman@stanford.edu.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology*; D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007155:Immunologic Factors / Q000008:administration & dosage; D056747:Immunomodulation / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000069462:Dimethyl Fumarate
keywords: EAE; M2 monocytes; Nrf2; dimethyl fumarate; multiple sclerosis