title: Erythropoietin is a hypoxia inducible factor-induced protective molecule in experimental autoimmune neuritis.
abstract: Experimental autoimmune neuritis (EAN), an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system, is characterized by self-limitation. Here we investigated the regulation and contribution of erythropoietin (EPO) in EAN self-limitation. In EAN sciatic nerves, hypoxia, and protein and mRNA levels of hypoxia-inducible factor 1α (HIF-1α), HIF-2α, EPO and EPO receptor (EPOR) were induced in parallel at disease peak phase but reduced at recovery periods. Further, the deactivation of HIF reduced EAN-induced EPO/EPOR upregulation in EAN, suggesting the central contribution of HIF to EPO/EPOR induction. The deactivation of EPOR signalling exacerbated EAN progression, implying that endogenous EPO contributed to EAN recovery. Exogenous EPO treatment greatly improved EAN recovery. In addition, EPO was shown to promote Schwann cell survival and myelin production. In EAN, EPO treatment inhibited lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3(+)/CD4(+) regulatory T cells and decrease of IFN-γ(+)/CD4(+) Th1 cells. Furthermore, EPO inhibited inflammatory macrophage activation and promoted its phagocytic activity. In summary, our data demonstrated that EPO was induced in EAN by HIF and contributed to EAN recovery, and endogenous and exogenous EPO could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that EPO contributes to the self-recovery of EAN and could be a potent candidate for treatment of autoimmune neuropathies.
authors.affiliation: Institute of Immunology, Third Military Medical University of PLA, 30 Gaotanyan Main Street, Chongqing 400038, People's Republic of China.
authors.forename: Bangwei
authors.initials: B
authors.lastname: Luo
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Xiong
authors.forename: Hermann J
authors.initials: HJ
authors.lastname: Schluesener
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004921:Erythropoietin / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D017467:Receptors, Erythropoietin / Q000276:immunology / Q000378:metabolism; D012583:Schwann Cells / Q000276:immunology / Q000378:metabolism; D012584:Sciatic Nerve / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017467:Receptors, Erythropoietin; D000099162:Endothelial PAS Domain-Containing Protein 1