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Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms.
J Neuroinflammation 2017; 14(1):202JN

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.

Authors+Show Affiliations

Department of Internal Medicine, Section of Clinical Immunology, University Hospital Zürich, Zurich, Switzerland.Institute of Veterinary Physiology and Zurich Center of Integrative Human Physiology (ZIHP), Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland.Department of Neurosurgery, University Hospital Zurich, CH-8006, Zurich, Switzerland.Institute of Veterinary Physiology and Zurich Center of Integrative Human Physiology (ZIHP), Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru.Institute of Veterinary Physiology and Zurich Center of Integrative Human Physiology (ZIHP), Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, CH-8057, Zurich, Switzerland. larao@access.uzh.ch.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29029628

Citation

Moransard, M, et al. "Erythropoietin Reduces Experimental Autoimmune Encephalomyelitis Severity Via Neuroprotective Mechanisms." Journal of Neuroinflammation, vol. 14, no. 1, 2017, p. 202.
Moransard M, Bednar M, Frei K, et al. Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms. J Neuroinflammation. 2017;14(1):202.
Moransard, M., Bednar, M., Frei, K., Gassmann, M., & Ogunshola, O. O. (2017). Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms. Journal of Neuroinflammation, 14(1), p. 202. doi:10.1186/s12974-017-0976-5.
Moransard M, et al. Erythropoietin Reduces Experimental Autoimmune Encephalomyelitis Severity Via Neuroprotective Mechanisms. J Neuroinflammation. 2017 Oct 13;14(1):202. PubMed PMID: 29029628.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms. AU - Moransard,M, AU - Bednar,M, AU - Frei,K, AU - Gassmann,M, AU - Ogunshola,O O, Y1 - 2017/10/13/ PY - 2017/06/23/received PY - 2017/10/03/accepted PY - 2017/10/15/entrez PY - 2017/10/17/pubmed PY - 2018/6/7/medline KW - EAE KW - Epo KW - Experimental autoimmune encephalomyelitis KW - Immunomodulation KW - Multiple sclerosis KW - Myelin KW - Neuroprotection SP - 202 EP - 202 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 14 IS - 1 N2 - 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/29029628/Erythropoietin_reduces_experimental_autoimmune_encephalomyelitis_severity_via_neuroprotective_mechanisms_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0976-5 DB - PRIME DP - Unbound Medicine ER -