Abstract
BackgroundGuillain–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.MethodsUsing 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.ResultsDMF 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.ConclusionsTaken together, our data demonstrate that DMF can effectively suppress EAN, and the mechanism involves altering the balance of M1/M2 macrophages and attenuating inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0559-x) contains supplementary material, which is available to authorized users.
Highlights
Guillain–Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots
We have demonstrated that Dimethyl fumarate (DMF) promotes experimental autoimmune neuritis (EAN) amelioration through a nuclear factor erythroid-derived 2-related factor 2 (Nrf2)/HO-1-mediated phenotypic shift in macrophages
The anti-inflammatory effects of DMF improve the environmental milieu in immune organ and indirectly exert neuroprotective effects
Summary
Guillain–Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. The potential mechanism underlying the effect of DMF in GBS animal model experimental autoimmune neuritis (EAN) is unclear. Guillain–Barré syndrome (GBS), known as an acute inflammatory disorder in the peripheral nervous system (PNS), can cause rapidly progressive, symmetrical weakness of the extremities [1]. Proven effective immunotherapies for GBS are plasma exchange and intravenous treatment with immunoglobulin G [1]. Experimental autoimmune neuritis (EAN), a wellknown animal model of GBS, effectively mimics clinical, histopathological, and electrophysiological features of GBS. Pro-inflammatory cytokines including IL-6, IFN-γ, IL-17, and TNF-α, mostly secreted by Th1 and Th17 cells, predominate in sciatic nerves and lymphoid organs during the acute phase of GBS and contribute to inflammatory impairment of peripheral nerves, whereas anti-inflammatory cytokines such as IL-4 and IL-10, mainly secreted by Th2 cells, are proven beneficial for the protection of inflammatory impairment of peripheral nerves [4, 5]
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