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

被引:78
作者
Han, Ranran [1 ]
Xiao, Jinting [1 ]
Zhai, Hui [1 ]
Hao, Junwei [1 ]
机构
[1] Tianjin Med Univ, Gen Hosp, Tianjin Neurol Inst, Dept Neurol, Anshan Rd, Tianjin 300052, Peoples R China
来源
JOURNAL OF NEUROINFLAMMATION | 2016年 / 13卷
基金
中国国家自然科学基金;
关键词
Experimental autoimmune neuritis; Macrophages; Dimethyl fumarate; Guillain-Barre syndrome; Cytokine; GUILLAIN-BARRE-SYNDROME; HEME OXYGENASE-1/CARBON MONOXIDE; REMITTING MULTIPLE-SCLEROSIS; TRANSCRIPTION FACTOR NRF2; ACID ESTERS; INTRACEREBRAL HEMORRHAGE; M2; MACROPHAGES; DAMAGE; ACTIVATION; PLASTICITY;
D O I
10.1186/s12974-016-0559-x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: Guillain-Barre 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-gamma, TNF-alpha, 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.
引用
收藏
页数:14
相关论文
共 44 条
[1]   Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm [J].
Biswas, Subhra K. ;
Mantovani, Alberto .
NATURE IMMUNOLOGY, 2010, 11 (10) :889-896
[2]   Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview [J].
Bomprezzi, Roberto .
THERAPEUTIC ADVANCES IN NEUROLOGICAL DISORDERS, 2015, 8 (01) :20-30
[3]   Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE [J].
Chen, Hui ;
Assmann, Julian C. ;
Krenz, Antje ;
Rahman, Mahbubur ;
Grimm, Myriam ;
Karsten, Christian M. ;
Koeh, Joerg ;
Offermanns, Stefan ;
Wettschureck, Nina ;
Schwaninger, Markus .
JOURNAL OF CLINICAL INVESTIGATION, 2014, 124 (05) :2188-2192
[4]   Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis [J].
Fox, Robert J. ;
Miller, David H. ;
Phillips, J. Theodore ;
Hutchinson, Michael ;
Havrdova, Eva ;
Kita, Mariko ;
Yang, Minhua ;
Raghupathi, Kartik ;
Novas, Mark ;
Sweetser, Marianne T. ;
Viglietta, Vissia ;
Dawson, Katherine T. .
NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (12) :1087-1097
[5]   Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells [J].
Ghoreschi, Kamran ;
Brueck, Juergen ;
Kellerer, Christina ;
Deng, Caishu ;
Peng, Haiyan ;
Rothfuss, Oliver ;
Hussain, Rehana Z. ;
Gocke, Anne R. ;
Respa, Annedore ;
Glocova, Ivana ;
Valtcheva, Nadejda ;
Alexander, Eva ;
Feil, Susanne ;
Feil, Robert ;
Schulze-Osthoff, Klaus ;
Rupec, Rudolf A. ;
Lovett-Racke, Amy E. ;
Dringen, Ralf ;
Racke, Michael K. ;
Roecken, Martin .
JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (11) :2291-2303
[6]   Alternative activation of macrophages [J].
Gordon, S .
NATURE REVIEWS IMMUNOLOGY, 2003, 3 (01) :23-35
[7]   THE ROLE OF MACROPHAGES AND EICOSANOIDS IN THE PATHOGENESIS OF EXPERIMENTAL ALLERGIC NEURITIS - SERIAL CLINICAL, ELECTROPHYSIOLOGICAL, BIOCHEMICAL AND MORPHOLOGICAL OBSERVATIONS [J].
HARTUNG, HP ;
SCHAFER, B ;
HEININGER, K ;
STOLL, G ;
TOYKA, KV .
BRAIN, 1988, 111 :1039-1059
[8]   Guillain-Barre syndrome [J].
Hughes, RAC ;
Cornblath, DR .
LANCET, 2005, 366 (9497) :1653-1666
[9]   Immunotherapy for Guillain-Barre syndrome:: a systematic review [J].
Hughes, Richard A. C. ;
Swan, Anthony V. ;
Raphael, Jean-Claude ;
Annane, Djillali ;
van Koningsveld, Rinske ;
van Doorn, Pieter A. .
BRAIN, 2007, 130 :2245-2257
[10]   The transcription factor Nrf2 is a therapeutic target against brain inflammation [J].
Innamorato, Nadia G. ;
Rojo, Ana I. ;
Garcia-Yaguee, Angel J. ;
Yamamoto, Masayuki ;
de Ceballos, Maria L. ;
Cuadrado, Antonio .
JOURNAL OF IMMUNOLOGY, 2008, 181 (01) :680-689