Abstract
Autoimmune uveitis is an inflammatory disease of the eye and is one of the major causes of blindness worldwide. Experimental autoimmune uveoretinitis (EAU) constitutes an animal disease model of human endogenous uveitis. In our study, we investigated the immunomodulatory effect of dimethyl fumarate (DMF) using bovine retinal extract-induced uveitis in a Female Wistar rats. To evaluate the in vivo efficacy, Female Wistar rats were divided into seven experimental groups: control group (n = 5), consisting of non-immunized animals; Uveoretinitis (n = 5), and DMF/Uveoretinitis groups (n = 15), which received a subcutaneous injection of bovine retinal extract emulsified in complete Freund’s adjuvant; MC group (n = 5), treated by daily intragastric administration of methylcellulose 0.08% in tap water; DMF group, consisting of control positive group, rats received daily oral gavage administration of 500 μL of dimethyl fumarate at 100 mg/Kg dissolved in 0.08% methylcellulose in tap water (n = 5). On day 14 post immunization, the rats were then euthanized and associated indications were investigated to evaluate the therapeutic efficacy. Nitric oxide (NO) and TNF-α were assessed in plasma. Meanwhile, eyes were collected for histological and immunohistochemical studies. The retinal expression of iNOS, CD68, CD20, CD25, CD4, and CD8 was examined. Interestingly, DMF enhanced a significant reduction of NO and TNF-α production in the treated group. This effect was strongly related to the histological structure of eyes improvement. In the same context, a significant decrease of iNOS, CD68, and CD20 expression and CD25 increase expression were reported in retinal tissue of DMF/Uveoretinitis group in comparison to the immunized group. Collectively, our results indicate that DMF treatment has a beneficial effect in experimental autoimmune uveoretinitis and could constitute a good candidate for monitoring an ocular inflammatory diseases.
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References
Agarwal RK, Caspi RR (2004) Rodent models of experimental autoimmune uveitis. Methods Mol Med 102:395–419
Agarwal RK, Silver PB, Caspi RR (2012) Rodent models of experimental autoimmune uveitis. Methods Mol Biol 900:443–469
Arroul-Lammali A, Djeraba Z, Belkhelfa M, Belguendouz H, Hartani D, Lahlou-Boukoffa OS, Touil-Boukoffa C (2012) Early involvement of nitric oxide in mechanisms of pathogenesis of experimental autoimmune uveitis induced by interphotoreceptor retinoid-binding protein (IRBP). J Fr Ophtalmol 35(4):251–259
Bansal S, Barathi AV, Iwata D, Agrawal R (2015) Experimental autoimmune uveitis and other animal models of uveitis: an update. Indian J Ophthalmol 63(3):211–218. https://doi.org/10.4103/0301-4738.156914
Calder VL, Zhao ZS, Wang Y, Barton K, Lightman SL (1993) Effects of CD8 depletion on retinal soluble antigen induced experimental autoimmune uveoretinitis. Immunology 79(2):255–262
Campolo M, Casili G, Biundo F, Crupi R, Cordaro M, Cuzzocrea S, Esposito E (2017) The neuroprotective effect of dimethyl fumarate in an MPTP-mouse model of parkinson’s disease: involvement of reactive oxygen species/nuclear factor-κB/nuclear transcription factor related to NF-E2. Antioxid Redox Signal 27:453–471
Casili G, Cordaro M, Impellizzeri D, Bruschetta G, Paterniti I, Cuzzocrea S, Esposito E (2015) Dimethyl fumarate reduces inflammatory responses in experimental colitis. J Crohn’s Colitis 10:472–483
Caspi RR (2002) Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis. Int Rev Immunol 21:197–208
Caspi RR, Roberge FG, Chan CC, Wiggert B, Chader GJ, Rozenszajn LA, Lando Z, Nussenblatt RB (1988) A new model of autoimmune disease: experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J Immunol 140:1490–1495
Dick AD, Forrester JV, Liversidge J, Cope AP (2004) The role of tumour necrosis factor (TNF-alpha) in experimental autoimmune uveoretinitis (EAU). Prog Retin Eye Res 23:617–637
Djeraba Z, Arroul-Lammali A, Medjber O, Belguendouz H, Hartani D, Lahlou-Boukoffa OS, Touil-Boukoffa C (2010) Nitric oxide, biomarker of experimental autoimmune uveitis induced by S antigen. J Fr Ophtalmol 33:693–700
Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M et al (2012) Placebo-controlled phase 3 study of oral BG12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097. https://doi.org/10.1056/NEJMoa1206328
Gery I, Nussenblatt RB, Chan CC, Caspi RR (2002) Autoimmune diseases of the eye. In: Theofilopoulos AN, Bona CA (eds) The molecular pathology of autoimmune diseases. Taylor and Francis, New York, pp 978–998
Gillard GO, Collette B, Anderson J, Chao J, Scannevin RH, Huss DJ, Fontenot JD (2015) DMF, but not other fumarates, inhibits NF-κB activity in vitro in an Nrf2-independent manner. J Neuroimmunol 283:74–85. https://doi.org/10.1016/j.jneuroim.2015.04.006
Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj KW, Tornatore C, Sweetser MT, Yang M, Sheikh SI et al (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. New Engl J Med 367:1098–1107. https://doi.org/10.1056/NEJMoa1114287
Heiligenhaus A, Miserocchi E, Heinz C, Gerloni V, Kotaniemi K (2011) Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab). Rheumatology 50(8):1390–1394. https://doi.org/10.1093/rheumatology/ker107
Jonas JB, Kreissig I, Degenring R (2003) Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 87:24–27
Kappos L, Gold R, Miller DH, MacManus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry AT, Yang M et al (2008) Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372:1463–1472
Kiefer R, Kieseier BC, Stoll G, Hartung HP (2001) The role of macrophages in immune-mediated damage to the peripheral nervous system. Prog Neurobiol 64:109–127. https://doi.org/10.1016/S0301-0082(00)00060-5
Kourakis S, Timpani CA, de Haan JB, Gueven N, Fischer D, Rybalka E (2020) Dimethyl fumarate and its esters: a drug with broad clinical utility? Pharmaceuticals 13:306. https://doi.org/10.3390/ph13100306
Labsi M, Khelifi L, Mezioug D, Soufli I, Touil-Boukoffa C (2016) Antihydatic and immunomodulatory effects of Punica granatum peel aqueous extract in a murine model of echinococcosis. Asian Pac J Trop Med 9(3):211–220
Labsi M, Soufli I, Khelifi L, Amir Z-C, Touil-Boukoffa C (2018) In vivo treatment with IL-17A attenuates hydatid cyst growth and liver fibrogenesis in an experimental model of echinococcosis. Acta Trop 181:6–10
Labsi M, Soufli I, Khelifi L, Amir Z-C, Touil-Boukoffa C (2019) A preventive effect of the combination of albendazole and pomegranate peel aqueous extract treatment in cystic echinococcosis mice model: an alternative approach. Acta Trop 197:105050
Lal R, Dhaliwal J, Dhaliwal N, Dharavath RN, Chopra K (2021) Activation of the Nrf2/HO-1 signaling pathway by dimethyl fumarate ameliorates complete Freund’s adjuvant-induced arthritis in rats. Eur J Pharmacol 899:174044
Lastres-Becker I, García-Yagüe AJ, Scannevin RH, Casarejos MJ, Kügler S, Rábano A, Cuadrado A (2016) Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in parkinson’s disease. Antioxid Redox Signal 25:61–77
Lee RW, Nicholson LB, Sen HN, Chan CC, Wei L, Nussenblatt RB, Dick AD (2014) Autoimmune and autoinflammatory mechanisms in uveitis. Semin Immunopathol 36:581–594. https://doi.org/10.1007/s00281-014-0433-9
Litjens NH, van Strijen E, van Gulpen C, Mattie H, van Dissel JT, Thio HB et al (2004) In vitro pharmacokinetics of anti-psoriatic fumaric acid esters. BMC Pharmacol 4:22. https://doi.org/10.1186/1471-2210-4-22
Michell-Robinson MA, Moore CS, Healy LM, Osso LA, Zorko N, Grouza V, Touil H, Poliquin-Lasnier L, Trudelle A-M, Giacomini PS, Bar-Or A, Antel JP (2015) Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis. Ann Clin Transl Neurol 3(1):27–41. https://doi.org/10.1002/acn3.270
Moshfeghi DM, Kaiser PK, Scott IU, Sears JE, Benz M, Sinesterra JP, Kaiser RS, Bakri SJ, Maturi RK, Belmont J, Beer PM, Murray TG, Quiroz-Mercado H, Mieler WF (2003) Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol 136:791–796. https://doi.org/10.1016/s0002-9394(03)00483-5
Nikoopour E, Lin CM, Sheskey S, Heckenlively JR, Lundy SK (2019) Immune cell infiltration into the eye is controlled by IL-10 in Recoverin-induced autoimmune retinopathy. J Immunol 202:1057–1068. https://doi.org/10.4049/jimmunol.1800574
Pitarokoili K, Bachir H, Sgodzai M, Grüter T, Haupeltshofer S, Duscha A, Pedreiturria X, Motte J, Gold R (2019) Induction of regulatory properties in the intestinal immune system by dimethyl fumarate in lewis rat experimental autoimmune neuritis. Front Immunol 10:2132. https://doi.org/10.3389/fimmu.2019.02132
Reszke R, Szepietowski JC (2020) A safety evaluation of dimethyl fumarate in moderate-to-severe psoriasis. Expert Opin Drug Saf 19:373–380
Shiratori K, Ohgami K, Bozhidarova I, Koyama Y, Yoshida K, Ohno S (2004) Inhibition of endotoxin-induced uveitis and potentiation of cyclooxygenase-2 protein expression by α-melanocyte–stimulating hormone. Invest Ophthalmol vis Sci 45:159–164
Stoof TJ, Flier J, Sampat S, Nieboer C, Tensen CP, Boorsma BM (2001) The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Br J Dermatol 144:1114–1120. https://doi.org/10.1046/j.1365-2133.2001.04220.x
Tian L, Yang P, Lei B, Shao J, Wang C, Xiang Q, Wei L, Peng Z, Kijlstra A (2011) AAV2-mediated subretinal gene transfer of hIFN-a attenuates experimental autoimmune Uveoretinitis in mice. PLoS ONE 6(5):19542
Touil-Boukoffa C, Bauvois B, Sanceau J, Hamrioui B, Weitzerbin J (1998) Production of nitric oxide (NO) in human hydatidosis: relationship between nitrite production and interferongamma levels. Biochemie 80:738–744
Touri K, Belguendouz H, Medjeber O, Djeraba Z, Lahmar K, Touil-Boukoffa C (2019) Propolis modulates NOS2/arginase-1 pathway in tropomyosin-induced experimental autoimmune uveitis. Inflammopharmacology 26:1293–1303
Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R (2010) Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1β, TNF-α and IL-6 in an in-vitro model of brain inflammation. J Neuroinflammation 7:30
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The author would like to thank Leila Daiah and Soraya Houmel for their technical help.
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Labsi, M., Soufli, I., Belguendouz, H. et al. Beneficial effect of dimethyl fumarate on experimental autoimmune uveitis is dependent of pro-inflammatory markers immunomodulation. Inflammopharmacol 29, 1389–1398 (2021). https://doi.org/10.1007/s10787-021-00864-1
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DOI: https://doi.org/10.1007/s10787-021-00864-1