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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
Article
  • 275 Downloads

Abstract

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.

Keywords

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

Notes

Compliance with Ethical Standards

Funding

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)

References

  1. 1.
    Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1(4):232–241.doi: 10.1016/S1474-4422(02)00102-3 PubMedCrossRefGoogle Scholar
  2. 2.
    Ciccarelli O, Barkhof F, Bodini B, De Stefano N, Golay X, Nicolay K, Pelletier D, Pouwels PJ et al (2014) Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurol 13(8):807–822. doi: 10.1016/S1474-4422(14)70101-2 PubMedCrossRefGoogle Scholar
  3. 3.
    Hammann KP, Hopf HC (1986) Monocytes constitute the only peripheral blood cell population showing an increased burst activity in multiple sclerosis patients. Int Arch Allergy Appl Immunol 81(3):230–234. doi: 10.1159/000234139 PubMedCrossRefGoogle Scholar
  4. 4.
    Koch MW, Ramsaransing GSM, Arutjunyan AV, Stepanov M, Teelken A, Heersema DJ, De Keyser J (2005) Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis. J Neurol 253(4):483–487. doi: 10.1007/s00415-005-0037-3 PubMedCrossRefGoogle Scholar
  5. 5.
    Nikić I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Brück W, Bishop D et al (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17(4):495–499. doi: 10.1038/nm.2324 PubMedCrossRefGoogle Scholar
  6. 6.
    Van Horssen J, Witte ME, Schreibelt G, de Vries HE (2011) Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta 1812(2):141–150. doi: 10.1016/j.bbadis.2010.06.011 PubMedCrossRefGoogle Scholar
  7. 7.
    Dimitrijević M, Kotur-Stevuljević J, Stojić-Vukanić Z, Vujnović I, Pilipović I, Nacka-Aleksić M, Leposavić G (2017) Sex difference in oxidative stress parameters in spinal cord of rats with experimental autoimmune encephalomyelitis: relation to neurological deficit. Neurochem Res 42:481–492. doi: 10.1007/s11064-016-2094-7 PubMedCrossRefGoogle Scholar
  8. 8.
    Croxford AL, Spath S, Becher B (2015) GM-CSF in neuroinflammation: licensing myeloid cells for tissue damage. Trends Immunol 36(10):651–662. doi: 10.1016/j.it.2015.08.004 PubMedCrossRefGoogle Scholar
  9. 9.
    Linker RA, Lee DS, Ryan S, Van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X et al (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134(3):678–692. doi: 10.1093/brain/awq386 PubMedCrossRefGoogle Scholar
  10. 10.
    Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K et al (2012) CONFIRM study investigators, placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367(12):1087–1097. doi: 10.1056/nejmoa1206328 PubMedCrossRefGoogle Scholar
  11. 11.
    Gold R, Kappos L, Arnold DI, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT et al (2012) DEFINE study investigators, placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367(12):1098–1107. doi: 10.1056/nejmoa1114287 PubMedCrossRefGoogle Scholar
  12. 12.
    Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, Cree BA, Sobel RA et al (2016) Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci U S A 113(17):4777–4782. doi: 10.1073/pnas.1603907113 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Pitarokoili K, Ambrosius B, Meyer D, Schrewe L, Gold R (2015) Dimethyl fumarate ameliorates Lewis rat experimental autoimmune neuritis and mediates axonal protection. PLoS One 10(11):e0143416. doi: 10.1371/journal.pone.0143416 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Stoof TJ, Flier J, Sampat S, Nieboer C, Tensen CP, Boorsma DM (2001) The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Br J Dermatol 144(6):1114–1120. doi: 10.1046/j.1365-2133.2001.04220.x PubMedCrossRefGoogle Scholar
  15. 15.
    Gerdes S, Shakery K, Mrowietz U (2007) Dimethylfumarate inhibits nuclear binding of nuclear factor κB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein beta in activated human T cells. Br J Dermatol 156(5):838–842. doi: 10.1111/j.1365-2133.2007.07779.x PubMedCrossRefGoogle Scholar
  16. 16.
    Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284(20):13291–13295. doi: 10.1074/jbc.r900010200 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S et al (2012) Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 341(1):274–284. doi: 10.1124/jpet.111.190132 PubMedCrossRefGoogle Scholar
  18. 18.
    Gill AJ, Kolson DL (2013) Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy. Crit Rev Immunol 33(4):307–359. doi: 10.1615/CritRevImmunol.2013007247 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Liu GH, Qu J, Shen X (2008) NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim Biophy Acta 1783(5):713–727. doi: 10.1016/j.bbamcr.2008.01.002 CrossRefGoogle Scholar
  20. 20.
    Bove R, Chitnis T (2013) Sexual disparities in the incidence and course of MS. Clin Immunol 149(2):201–210. doi: 10.1016/j.clim.2013.03.005 PubMedCrossRefGoogle Scholar
  21. 21.
    Giatti S, D’Intino G, Maschi O, Pesaresi M, Garcia-Segura LM, Calza L, Caruso D, Melcangi RC (2010) Acute experimental autoimmune encephalomyelitis induces sex dimorphic changes in neuroactive steroid levels. Neurochem Int 56(1):118–127. doi: 10.1016/j.neuint.2009.09.009 PubMedCrossRefGoogle Scholar
  22. 22.
    Nacka-Aleksić M, Djikić J, Pilipović I, Stojić-Vukanić Z, Kosec D, Bufan B, Arsenović-Ranin N, Dimitrijević M et al (2015) Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level. Brain Behav Immun 49:101–118. doi: 10.1016/j.bbi.2015.04.017 PubMedCrossRefGoogle Scholar
  23. 23.
    Kawakami N, Lassmann S, Li Z, Odoardi F, Ritter T, Ziemssen T, Klinkert WE, Ellwart JW et al (2004) The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis. J Exp Med 199(2):185–197. doi: 10.1084/jem.20031064 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Zagni E, Simoni L, Colombo D (2016) Sex and gender differences in central nervous system-related disorders. Neurosci J 2016:2827090. doi: 10.1155/2016/2827090 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Li R, Sun X, Shu Y, Mao Z, Xiao L, Qiu W, Lu Z, Hu X (2017) Sex differences in outcomes of disease-modifying treatments for multiple sclerosis: a systematic review. Mult Scler Relat Dis 12:23–28. doi: 10.1016/j.msard.2017.01.001 CrossRefGoogle Scholar
  26. 26.
    Bar-Or A, Gold R, Kappos L, Arnold DL, Giovannoni G, Selmaj K, O'Gorman J, Stephan M et al (2013) Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol 260:2297–2305. doi: 10.1007/s00415-013-6954-7 PubMedCrossRefGoogle Scholar
  27. 27.
    Hutchinson M, Fox RJ, Miller DH, Phillips JT, Kita M, Havrdova E, O’Gorman J, Zhang R et al (2013) Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol 260:2286–2296. doi: 10.1007/s00415-013-6968-1 PubMedCrossRefGoogle Scholar
  28. 28.
    Djikić J, Nacka-Aleksić M, Pilipović I, Stojić-Vukanić Z, Bufan B, Kosec D, Dimitrijević M, Leposavić G (2014) Age-associated changes in rat immune system: Lessons learned from experimental autoimmune encephalomyelitis. Exp Gerontol 58:179–197. doi: 10.1016/j.exger.2014.08.005 PubMedCrossRefGoogle Scholar
  29. 29.
    Ridderstad Wollberg A, Ericsson-Dahlstrand A, Juréus A, Ekerot P, Simon S, Nilsson M, Wiklund S-J, Berg A-L et al (2014) Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis. PNAS 111(14):5409–5414. doi: 10.1073/pnas.1316510111 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Dimitrijević M, Aleksić I, Vujić V, Stanojević S, Pilipović P, von Hörsten S, Leposavić G (2014) Peritoneal exudate cells from long-lived rats exhibit increased IL-10/IL-1β expression ratio and preserved NO/urea ratio following LPS-stimulation in vitro. Age (Dordr) 36(4):9696. doi: 10.1007/s11357-014-9696-2 CrossRefGoogle Scholar
  31. 31.
    Auclair C, Voisin E (1985) Nitroblue tetrazolium reduction. In: Greenwald RA (ed) CRC handbook of methods for oxygen radical research. CRC Press, Boca Raton, pp. 123–132Google Scholar
  32. 32.
    Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247(10):3170–3175PubMedGoogle Scholar
  33. 33.
    Girotti MJ, Khan N, McLellan BA (1991) Early measurement of systemic lipid peroxidation products in the plasma of major blunt trauma patients. J Trauma 31(1):32–35. doi: 10.1097/00005373-199101000-00007 PubMedCrossRefGoogle Scholar
  34. 34.
    Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49(5):1304–1313. doi: 10.1038/ki.1996.186 PubMedCrossRefGoogle Scholar
  35. 35.
    Erel O (2005) A new automated colorimetric method for measuring total oxidant status. Clin Biochem 38(12):1103–1111. doi: 10.1016/j.clinbiochem PubMedCrossRefGoogle Scholar
  36. 36.
    Kotur-Stevuljevic J, Bogavac-Stanojevic N, Jelic-Ivanovic Z, Stefanovic A, Gojkovic T, Joksic J, Sopic M, Gulan B et al (2015) Oxidative stress and paraoxonase 1 status in acute ischemic stroke patients. Atherosclerosis 241(1):192–198. doi: 10.1016/j.atherosclerosis.2015.05.016 PubMedCrossRefGoogle Scholar
  37. 37.
    Erel O (2004) A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 37(4):277–285. doi: 10.1016/j.clinbiochem.2003.11.015 PubMedCrossRefGoogle Scholar
  38. 38.
    Alamdari DH, Paletas K, Pegiou T, Sarigianni M, Befani C, Koliakos G (2007) A novel assay for the evaluation of the prooxidant-antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients. Clin Biochem 40(3–4):248–254. doi: 10.1016/j.clinbiochem.2006.10.017 PubMedCrossRefGoogle Scholar
  39. 39.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  40. 40.
    Fillmore PD, Blankenhorn EP, Zachary JF, Teuscher C (2004) Adult gonadal hormones selectively regulate sexually dimorphic quantitative traits observed in experimental allergic encephalomyelitis. Am J Pathol 164(1):167–175. doi: 10.1016/S0002-9440(10)63107-0 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Damsker JM, Hansen AM, Caspi RR (2010) Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci 1183:211–221. doi: 10.1111/j.1749-6632.2009.05133.x PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Flügel A, Berkowicz T, Ritter T, Labeur M, Jenne DE, Li Z, Ellwart JW, Willem M et al (2001) Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 14(5):547–560. doi: 10.1016/S1074-7613(01)00143-1 PubMedCrossRefGoogle Scholar
  43. 43.
    Treumer F, Zhu K, Gläser R, Mrowietz U (2003) Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol 121(6):1383–1388. doi: 10.1111/j.1523-1747.2003.12605.x PubMedCrossRefGoogle Scholar
  44. 44.
    Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12(6):560–567. doi: 10.1038/ni.2027 PubMedCrossRefGoogle Scholar
  45. 45.
    El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel BN et al (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12(6):568–575. doi: 10.1038/ni.2031 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Stojić-Vukanić Z, Pilipović I, Vujnović I, Nacka-Aleksić M, Petrović R, Arsenović-Ranin N, Dimitrijević M, Leposavić G (2016) GM-CSF-producing Th cells in rats sensitive and resistant to experimental autoimmune encephalomyelitis. PLoS One 11(11):e0166498. doi: 10.1371/journal.pone.0166498 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L et al (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature 467(7318):967–971. doi: 10.1038/nature09447 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969. doi: 10.1038/nri2448 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Gandhi R, Laroni A, Weiner HL (2010) Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol 221(1–2):7–14. doi: 10.1016/j.jneuroim.2009.10.015 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Murphy AC, Lalor SJ, Lynch MA, Mills KH (2010) Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun 24(4):641–651. doi: 10.1016/j.bbi.2010.01.014 PubMedCrossRefGoogle Scholar
  51. 51.
    Han R, Xiao J, Zhai H, Hao J (2016) 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. J Neuroinflammation 13(1):97. doi: 10.1186/s12974-016-0559-x PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Bullard DC, Hu X, Schoeb TR, Axtell RC, Raman C, Barnum SR (2005) Critical requirement of CD11b (Mac-1) on T cells and accessory cells for development of experimental autoimmune encephalomyelitis. J Immunol 175(10):6327–6333. doi: 10.4049/jimmunol.175.10.6327 PubMedCrossRefGoogle Scholar
  53. 53.
    Mindur JE, Ito N, Dhib-Jalbut S, Ito K (2014) Early treatment with anti-VLA-4 mAb can prevent the infiltration and/or development of pathogenic CD11b+ CD4+ T cells in the CNS during progressive EAE. PLoS One 9(6):e99068. doi: 10.1371/journal.pone.0099068 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Zhang Z, Zhang ZY, Schittenhelm J, Wu Y, Meyermann R, Schluesener HJ (2011) Parenchymal accumulation of CD163+ macrophages/microglia in multiple sclerosis brains. J Neuroimmunol 237(1–2):73–79. doi: 10.1016/j.jneuroim.2011.06.006 PubMedCrossRefGoogle Scholar
  55. 55.
    Fehr E-M, Kierschke S, Max R, Gerber A, Lorenz H-M, Schiller M (2009) Apototic cell-derived membrane vesicles induce CD83 expression on human mdDC. Autoimmunity 42(4):322–324. doi: 10.1080/08916930902832173 PubMedCrossRefGoogle Scholar
  56. 56.
    Stöger JL, Goossens P, de Winther MP (2010) Macrophage heterogeneity: relevance and functional implications in atherosclerosis. Curr Vasc Pharmacol 8(2):233–248. doi: 10.2174/157016110790886983 PubMedCrossRefGoogle Scholar
  57. 57.
    Munder M, Eichmann K, Morán JM, Centeno F, Soler G, Modolell M (1999) Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J Immunol 163(7):3771–3777PubMedGoogle Scholar
  58. 58.
    Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98. doi: 10.1186/1742-2094-11-98 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Ahn M, Yang W, Kim H, Jin JK, Moon C, Shin T (2012) Immunohistochemical study of arginase-1 in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis. Brain Res 1453:77–86. doi: 10.1016/j.brainres.2012.03.023 PubMedCrossRefGoogle Scholar
  60. 60.
    Mattila JT, Ojo OO, Kepka-Lenhart D, Marino S, Kim JH, Eum SY, Via LE, Barry CE 3rd et al (2013) Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol 191(2):773–784. doi: 10.4049/jimmunol.1300113 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Honorat A, Kinoshita M, Okuno T, Takata K, Koda T, Tada S, Shirakura T, Fujimura H et al (2013) Xanthine oxidase mediates axonal and myelin loss in a murine model of multiple sclerosis. PLoS One 8:e71329. doi: 10.1371/journal.pone.0071329 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Fukai T, Ushio-Fukai M (2011) Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15(6):1583–1606. doi: 10.1089/ars.2011.3999 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Huang H, Taraboletti A, Shriver LP (2015) Dimethyl fumarate modulates antioxidant and lipid metabolism in oligodendrocytes. Redox Biol 5:169–175. doi: 10.1016/j.redox.2015.04.011 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, Köhl J, Offermanns S et al (2014) Hydrocarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE. J Clin Invest 124(5):2188–21192. doi: 10.1172/JCI72151 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Lim JL, Van der Pol SMA, Di Dio F, Van het Hof B, Kooij G, De Vries HE, Van Horssen J (2016) Protective effects of monomethyl fumarate at the inflamed blood–brain barrier. Microvasc Res 105:61–69. doi: 10.1016/j.mvr.2015.12.003 PubMedCrossRefGoogle Scholar
  66. 66.
    Wang L-F, Yokoyama KK, Lin C-L, Chen T-Y, Hsiao H-W, Chiang P-C, Hsu C (2016) Knockout of ho-1 protects the striatum from ferrous iron-induced injury in a male-specific manner in mice. Sci Reports 6:26358. doi: 10.1038/srep26358 CrossRefGoogle Scholar
  67. 67.
    Rohrer PR, Rudraiah S, Goedken MJ, Manautou JE (2014) Is nuclear factor erythroid 2–related factor 2 responsible for sex differences in susceptibility to acetaminophen-induced hepatotoxicity in mice? Drug Metab Dispos 42(10):1663–1674. doi: 10.1124/dmd.114.059006 PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kratschmar DV, Calabrese D, Walsh J, Lister A, Birk J, Appenzeller-Herzog C, Moulin P, Goldring CE et al (2012) Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11β-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS One 7(5):e36774. doi: 10.1371/journal.pone.0036774 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Rubant SA, Ludwig RJ, Diehl S, Hardt K, Kaufmann R, Pfeilschifter JM, Boehncke WH (2008) Dimethylfumarate reduces leukocyte rolling in vivo through modulation of adhesion molecule expression. J Invest Dermatol 128(2):326–331. doi: 10.1038/sj.jid.5700996 PubMedCrossRefGoogle Scholar
  70. 70.
    Wallbrecht K, Drick N, Hund AC, Schon MP (2011) Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions. Exp Dermatol 20(12):980–985. doi: 10.1111/j.1600-0625.2011.01376.x PubMedCrossRefGoogle Scholar
  71. 71.
    Dehmel T, Dobert M, Pankratz S, Leussink VI, Hartung HP, Wiendl H, Kieseier BC (2014) Monomethylfumarate reduces in vitro migration of mononuclear cells. Neurol Sci 35(7):1121–1125. doi: 10.1007/s10072-014-1663-2 PubMedCrossRefGoogle Scholar
  72. 72.
    Zhao X, Eghbali-Webb M (2002) Gender-related differences in basal and hypoxia-induced activation of signal transduction pathways controlling cell cycle progression and apoptosis, in cardiac fibroblasts. Endocrine 18(2):137–145. doi: 10.1385/ENDO:18:2:137 PubMedCrossRefGoogle Scholar
  73. 73.
    Ritzel RM, Capozzi LA, McCullough LD (2013) Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke. Horm Behav 63(2):238–253. doi: 10.1016/j.yhbeh.2012.04.007 PubMedCrossRefGoogle Scholar
  74. 74.
    Ebihara S, Tajima H, Ono M (2016) Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis. Arthritis Res Ther 18(1):139. doi: 10.1186/s13075-016-1039-5 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kopf M, Ruedl C, Schmitz N, Gallimore A, Lefrang K, Ecabert B, Odermatt B, Bachmann MF (1999) OX40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL responses after virus infection. Immunity 11(6):699–708. doi: 10.1016/S1074-7613(00)80144-2 PubMedCrossRefGoogle Scholar
  76. 76.
    Fujimoto Y, Tedder TF (2006) CD83: a regulatory molecule of the immune system with great potential for therapeutic application. J Med Dent Sci 53(2):85–91PubMedGoogle Scholar
  77. 77.
    Hock BD, Kato M, McKenzie JL, Hart DN (2001) A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera. Int Immunol 13(7):959–967. doi: 10.1093/intimm/13.7.959 PubMedCrossRefGoogle Scholar
  78. 78.
    Lechmann M, Krooshoop DJ, Dudziak D, Kremmer E, Kuhnt C, Figdor CG, Schuler G, Steinkasserer A (2001) The extracellular domain of CD83 inhibits dendritic cell-mediated T cell stimulation and binds to a ligand on dendritic cells. J Exp Med 194(12):1813–1821PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Sénéchal B, Boruchov AM, Reagan JL, Hart DN, Young JW (2004) Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 103(11):4207–4215. doi: 10.1182/blood-2003-12-4350 PubMedCrossRefGoogle Scholar
  80. 80.
    Zinser E, Lechmann M, Golka A, Lutz MB, Steinkasserer A (2004) Prevention and treatment of experimental autoimmune encephalomyelitis by soluble CD83. J Exp Med 200(3):345–351. doi: 10.1084/jem.20030973 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Bates JM, Flanagan K, Mo L, Ota N, Ding J, Ho S, Liu S, Roose-Girma M et al (2015) Dendritic cell CD83 homotypic interactions regulate inflammation and promote mucosal homeostasis. Mucosal Immunol 8(2):414–428. doi: 10.1038/mi.2014.79 PubMedCrossRefGoogle Scholar
  82. 82.
    Ghoreschi K, Bruck J, Kellerer C, Deng C, Peng H, Rothfuss O, Hussain RZ, Gocke AR et al (2011) Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 208(11):2291–2303. doi: 10.1084/jem.20100977 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Morgan MJ, Liu ZG (2011) Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res 21(1):103–115. doi: 10.1038/cr.2010.178 PubMedCrossRefGoogle Scholar
  84. 84.
    Mühl H, Bachmann M, Pfeilschifter J (2011) Inducible NO synthase and antibacterial host defence in times of Th17/Th22/T22 immunity. Cell Microbiol 13(3):340–348. doi: 10.1111/j.1462-5822.2010.01559.x PubMedCrossRefGoogle Scholar
  85. 85.
    Bonacasa B, Perez C, Salom MG, Lopez B, Saez-Belmonte F, Martinez P, Casas T, Fenoy FJ et al (2013) Sexual dimorphism in renal heme-heme oxygenase system in the streptozotocin diabetic rats. Curr Pharm Des 19(15):2678–2686. doi: 10.2174/1381612811319150002 PubMedCrossRefGoogle Scholar
  86. 86.
    Schmidt TJ, Ak M, Mrowietz U (2007) Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-L-cysteine-preparation of S-substituted thiosuccinic acid esters. Bioorg Med Chem 15(1):333–342. doi: 10.1016/j.bmc.2006.09.053 PubMedCrossRefGoogle Scholar
  87. 87.
    Stein DG (2001) Brain damage, sex hormones and recovery: a new role for progesterone and estrogen. Trends Neurosci 24(7):386–391. doi: 10.1016/S0166-2236(00)01821-X PubMedCrossRefGoogle Scholar
  88. 88.
    Penaloza C, Estevez B, Orlanski S, Sikorska M, Walker R, Smith C, Smith B, Lockshin RA et al (2009) Sex of the cell dictates its response: Differential gene expression and sensitivity to cell death inducing stress in male and female cells. FASEB J 23(6):1869–1879. doi: 10.1096/fj.08-119388 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Cichocki JA, Smith GJ, Mendoza R, Buckpitt AR, Van Winkle LS, Morris JB (2014) Sex differences in the acute nasal antioxidant/antielectrophilic response of the rat to inhaled naphthalene. Toxicol Sci 139(1):234–244. doi: 10.1093/toxsci/kfu031 PubMedCrossRefGoogle Scholar
  90. 90.
    Nie X, Lowe DW, Rollins LG, Bentzley J, Fraser JL, Martin R, Singh I, Jenkins D (2016) Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia. Neurosci Res 108:24–33. doi: 10.1016/j.neures.2016.01.008 PubMedPubMedCentralCrossRefGoogle Scholar

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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