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Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms

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dc.contributor.author Moransard, M.
dc.contributor.author Bednar, M.
dc.contributor.author Frei, K.
dc.contributor.author Gassmann, M.
dc.contributor.author Ogunshola, O. O.
dc.date.accessioned 2019-01-25T15:18:34Z
dc.date.available 2019-01-25T15:18:34Z
dc.date.issued 2017
dc.identifier.uri https://hdl.handle.net/20.500.12866/4646
dc.description.abstract BACKGROUND: Treatment with erythropoietin (Epo) in experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis (MS), has consistently been shown to ameliorate disease progression and improve overall outcome. The effect has been attributed to modulation of the immune response and/or preservation of the central nervous system (CNS) tissue integrity. It remains unclear, however, if (a) Epo acts primarily in the CNS or the periphery and if (b) Epo's beneficial effect in EAE is mainly due to maintaining CNS tissue integrity or to modulation of the immune response. If Epo acts primarily by modulating the immune system, where is this modulation required? In the periphery, the CNS or both? METHODS: To address these questions, we used two well-characterized transgenic mouse strains that constitutively overexpress recombinant human Epo (rhEpo) either systemically (tg6) or in CNS only (tg21) in a MOG-induced EAE model. We assessed clinical severity, disease progression, immunomodulation, and CNS tissue integrity, including neuronal survival. RESULTS: Although disease onset remained unaffected, EAE progression was alleviated in transgenic animals compared to controls with both lines performing equally well showing that expression of Epo in the periphery is not required; Epo expression in the CNS is sufficient. Immunomodulation was observed in both strains but surprisingly the profile of modulation differed substantially between strains. Modulation in the tg21 strain was limited to a reduction in macrophages in the CNS, with no peripheral immunomodulatory effects observed. In contrast, in the tg6 strain, macrophages were upregulated in the CNS, and, in the periphery of this strain, T cells and macrophages were downregulated. The lack of a consistent immunomodulatory profile across both transgenic species suggests that immunomodulation by Epo is unlikely to be the primary mechanism driving amelioration of EAE. Finally, CNS tissue integrity was affected in all strains. Although myelin appeared equally damaged in all strains, neuronal survival was significantly improved in the spinal cord of tg21 mice, indicating that Epo may ameliorate EAE predominantly by protecting neurons. CONCLUSIONS: Our data suggests that moderate elevated brain Epo levels provide clinically significant neuroprotection in EAE without modulation of the immune response making a significant contribution. en_US
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartofseries Journal of Neuroinflammation
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Animals en_US
dc.subject Central Nervous System/metabolism/pathology en_US
dc.subject Cytokines/genetics/metabolism en_US
dc.subject Disease Models, Animal en_US
dc.subject EAE en_US
dc.subject Encephalomyelitis, Autoimmune, Experimental/chemically induced/pathology/therapy en_US
dc.subject Epo en_US
dc.subject Erythropoietin/genetics/metabolism en_US
dc.subject Experimental autoimmune encephalomyelitis en_US
dc.subject Female en_US
dc.subject Gene Expression Regulation/drug effects/genetics en_US
dc.subject Humans en_US
dc.subject Immunomodulation en_US
dc.subject Lymphocytes/pathology en_US
dc.subject Macrophages/metabolism/pathology en_US
dc.subject Mice en_US
dc.subject Mice, Inbred C57BL en_US
dc.subject Mice, Transgenic en_US
dc.subject Monocytes/pathology en_US
dc.subject Multiple sclerosis en_US
dc.subject Myelin en_US
dc.subject Myelin-Oligodendrocyte Glycoprotein/immunology/toxicity en_US
dc.subject Neurons/metabolism/pathology en_US
dc.subject Neuroprotection en_US
dc.subject Neuroprotection/drug effects/genetics/physiology en_US
dc.subject Peptide Fragments/immunology/toxicity en_US
dc.subject Proto-Oncogene Proteins c-sis/genetics/metabolism en_US
dc.subject Spleen/pathology en_US
dc.title Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1186/s12974-017-0976-5
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.01.03
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.25
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.01.04
dc.relation.issn 1742-2094


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