Erythropoietin: A Potent Inducer of Peripheral Immuno/Inflammatory Modulation in Autoimmune EAE

Ruirong Yuan,Yasuhiro Maeda,Wei Lu,Stuart Cook,Weiping Li,Peter Dowling,Jacques Zimmer

doi:10.1371/journal.pone.0001924

Abstract

BackgroundBeneficial effects of short-term erythropoietin (EPO) therapy have been demonstrated in several animal models of acute neurologic injury, including experimental autoimmune encephalomyelitis (EAE)-the animal model of multiple sclerosis. We have found that EPO treatment substantially reduces the acute clinical paralysis seen in EAE mice and this improvement is accompanied by a large reduction in the mononuclear cell infiltration and downregulation of glial MHC class II expression within the inflamed CNS. Other reports have recently indicated that peripherally generated anti-inflammatory CD4+Foxp3+ regulatory T cells (Tregs) and the IL17-producing CD4+ T helper cell (Th17) subpopulations play key antagonistic roles in EAE pathogenesis. However, no information regarding the effects of EPO therapy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged.Methods and FindingsWe first determined in vivo that EPO therapy markedly suppressed MOG specific T cell proliferation and sharply reduced the number of reactive dendritic cells (CD11c positive) in EAE lymph nodes during both inductive and later symptomatic phases of MOG35–55 induced EAE. We then determined the effect in vivo of EPO on numbers of peripheral Treg cells and Th17 cells. We found that EPO treatment modulated immune balance in both the periphery and the inflamed spinal cord by promoting a large expansion in Treg cells, inhibiting Th17 polarization and abrogating proliferation of the antigen presenting dendritic cell population. Finally we utilized tissue culture assays to show that exposure to EPO in vitro similarly downregulated MOG-specific T cell proliferation and also greatly suppressed T cell production of pro-inflammatory cytokines.ConclusionsTaken together, our findings reveal an important new locus whereby EPO induces substantial long-term tissue protection in the host through signaling to several critical subsets of immune cells that reside in the peripheral lymphatic system.

Highlights

Most autoreactive T cells are negatively selected and eliminated during thymic development in a process called central T cell tolerance [1,2]
Th17 cells are a unique subset of CD4+ TH cells and recent studies suggest that Th17 cells have an important pathogenic role in T cell mediated autoimmune disease and tissue inflammation [5,6,7,8,9]
Another distinct T cell population (CD4+Foxp3+) called regulatory T cells (Tregs) has attracted attention recently because it plays an important role in maintenance of peripheral tolerance and in controlling the destructive self-reactive T cells found in autoimmune animal models of arthritis, multiple sclerosis, diabetes, and inflammatory bowel disease [10,11,12]

Summary

Introduction

Most autoreactive T cells are negatively selected and eliminated during thymic development in a process called central T cell tolerance [1,2]. When abnormally activated by ‘‘self’’ antigens or mimics, these autoreactive T cells may attack self-organs thereby participating in the development of autoimmune disorders This fact is supported by the demonstrable ability to induce a variety of autoimmune diseases in rodents using appropriate immunization protocols. Th17 cells are a unique subset of CD4+ TH cells and recent studies suggest that Th17 cells have an important pathogenic role in T cell mediated autoimmune disease and tissue inflammation [5,6,7,8,9] Another distinct T cell population (CD4+Foxp3+) called regulatory T cells (Tregs) has attracted attention recently because it plays an important role in maintenance of peripheral tolerance and in controlling the destructive self-reactive T cells found in autoimmune animal models of arthritis, multiple sclerosis, diabetes, and inflammatory bowel disease [10,11,12]. No information regarding the effects of EPO therapy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged

Methods

Results

Conclusion