title: Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages.
abstract: BACKGROUND
  Guillain-Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. Dimethyl fumarate (DMF), a fumaric acid ester, exhibits various biological activities, including multiple immunomodulatory and neuroprotective effects. However, the potential mechanism underlying the effect of DMF in GBS animal model experimental autoimmune neuritis (EAN) is unclear.
  
  
  METHODS
  Using EAN, an established GBS model, we investigated the effect of DMF by assessing clinical score, histological staining and electrophysiological studies. Then, we further explored the potential mechanism by Western blot analysis, flow cytometry, fluorescence immunohistochemistry, PCR, and ELISA analysis. The Mann-Whitney U test was used to compare differences between control group and treatment groups where appropriate.
  
  
  RESULTS
  DMF treatment reduced the neurological deficits by ameliorating inflammatory cell infiltration and demyelination of sciatic nerves. In addition, DMF treatment decreased the level of pro-inflammatory M1 macrophages while increasing the number of anti-inflammatory M2 macrophages in the spleens and sciatic nerves of EAN rats. In RAW 264.7, a shift in macrophage polarization from M1 to M2 phenotype was demonstrated to be depended on DMF application. In sciatic nerves, DMF treatment elevated the level of the antioxidant transcription factor nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and its target gene hemoxygenase-1 (HO-1) which could facilitate macrophage polarization toward M2 type. Moreover, DMF improved the inflammatory milieu in spleens of EAN rats, characterized by downregulation of messenger RNA (mRNA) of IFN-γ, TNF-α, IL-6, and IL-17 and upregulation of mRNA level of IL-4 and IL-10.
  
  
  CONCLUSIONS
  Taken together, our data demonstrate that DMF can effectively suppress EAN, and the mechanism involves altering the balance of M1/M2 macrophages and attenuating inflammation.
authors.affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road, Heping District, Tianjin, 300052, China.
authors.forename: Ranran
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road, Heping District, Tianjin, 300052, China.
authors.forename: Jinting
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road, Heping District, Tianjin, 300052, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhai
authors.affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Anshan Road, Heping District, Tianjin, 300052, China. hjw@tmu.edu.cn.
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004594:Electrophysiology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D051547:Heme Oxygenase-1; D000069462:Dimethyl Fumarate
keywords: Cytokine; Dimethyl fumarate; Experimental autoimmune neuritis; Guillain–Barré syndrome; Macrophages