Molecular Neurobiology

, Volume 55, Issue 5, pp 3755–3774 | Cite as

Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action

  • Zorica Stojić-Vukanić
  • Jelena Kotur-Stevuljević
  • Mirjana Nacka-Aleksić
  • Duško Kosec
  • Ivana Vujnović
  • Ivan Pilipović
  • Mirjana Dimitrijević
  • Gordana Leposavić


In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-γ+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCRαβ− microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCRαβ– cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage.


EAE Dimethyl fumarate Sexual dimorphism Pathogenic IL-17+ lymphocytes CD163+ phygocyting myeloid cells CD83 expression Oxidative stress 


Compliance with Ethical Standards


This study was funded by the Ministry of Education, Science and Technological Development of Republic of Serbia (grant numbers 175050 and 175035).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2017_595_Fig9_ESM.gif (31 kb)
Supplementary Fig. 1

DMF was more efficient in decreasing the frequency of CD11b+ cells among TCRαβ+ cells in spinal cord of male rats immunized for EAE. Flow cytometry dot plots indicate CD11b staining of TCRαβ+ lymphocytes retrieved at the peak of EAE from spinal cord (SC) of female and male rats administered with DMF (+DMF) or vehicle (−DMF). CD11b+ events were defined based on FMO control missing CD11b. Scatter plot indicates the frequency of CD11b+ cells among T lymphocytes retrieved from SC of female and male −DMF and +DMF rats. Results are from one of two similar experiments each comprising six rats/group. Data are presented as mean ± S.E.M. Two-way ANOVA showed significant interaction between the effect of treatment and sex for the frequency of CD11b+ T cells (F (1, 20) = 22.10; p ≤ 0.001). ***p ≤ 0.001 (GIF 30 kb)

12035_2017_595_MOESM1_ESM.tif (422 kb)
High Resolution (TIFF 422 kb)
12035_2017_595_Fig10_ESM.gif (8 kb)
Supplementary Fig. 2

Flow cytometry gating strategy for CD11b+CD45+TCRαβ− cells. Flow cytometry histogram indicates CD11b staining of CD45+TCRαβ− spinal cord cells gated as shown in corresponding flow cytometry dot plot. Subsequently, CD11b+ cells were selected and further analyzed for CD163 or CD83 expression, as displayed in Fig. 4 (GIF 7 kb)

12035_2017_595_MOESM2_ESM.tif (119 kb)
High Resolution (TIFF 118 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Zorica Stojić-Vukanić
    • 1
  • Jelena Kotur-Stevuljević
    • 2
  • Mirjana Nacka-Aleksić
    • 3
  • Duško Kosec
    • 4
  • Ivana Vujnović
    • 4
  • Ivan Pilipović
    • 4
  • Mirjana Dimitrijević
    • 5
  • Gordana Leposavić
    • 3
  1. 1.Department of Microbiology and Immunology, Faculty of PharmacyUniversity of BelgradeBelgradeSerbia
  2. 2.Department for Medical Biochemistry, Faculty of PharmacyUniversity of BelgradeBelgradeSerbia
  3. 3.Department of Physiology, Faculty of PharmacyUniversity of BelgradeBelgradeSerbia
  4. 4.Immunology Research Centre “Branislav Janković”Institute of Virology, Vaccines and Sera “Torlak”BelgradeSerbia
  5. 5.Department of Immunology, Institute for Biological Research “Siniša Stanković”University of BelgradeBelgradeSerbia

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