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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

IFN-γ protects from lethal IL-17 mediated viral encephalomyelitis independent of neutrophils

Authors: Carine Savarin, Stephen A Stohlman, David R Hinton, Richard M Ransohoff, Daniel J Cua, Cornelia C Bergmann

Published in: Journal of Neuroinflammation | Issue 1/2012

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Abstract

Background

The interplay between IFN-γ, IL-17 and neutrophils during CNS inflammatory disease is complex due to cross-regulatory factors affecting both positive and negative feedback loops. These interactions have hindered the ability to distinguish the relative contributions of neutrophils, Th1 and Th17 cell-derived effector molecules from secondary mediators to tissue damage and morbidity.

Methods

Encephalitis induced by a gliatropic murine coronavirus was used as a model to assess the direct contributions of neutrophils, IFN-γ and IL-17 to virus-induced mortality. CNS inflammatory conditions were selectively manipulated by adoptive transfer of virus-primed wild-type (WT) or IFN-γ deficient (GKO) memory CD4+ T cells into infected SCID mice, coupled with antibody-mediated neutrophil depletion and cytokine blockade.

Results

Transfer of GKO memory CD4+ T cells into infected SCID mice induced rapid mortality compared to recipients of WT memory CD4+ T cells, despite similar virus control and demyelination. In contrast to recipients of WT CD4+ T cells, extensive neutrophil infiltration and IL-17 expression within the CNS in recipients of GKO CD4+ T cells provided a model to directly assess their contribution(s) to disease. Recipients of WT CD4+ T cells depleted of IFN-γ did not express IL-17 and were spared from mortality despite abundant CNS neutrophil infiltration, indicating that mortality was not mediated by excessive CNS neutrophil accumulation. By contrast, IL-17 depletion rescued recipients of GKO CD4+ T cells from rapid mortality without diminishing neutrophils or reducing GM-CSF, associated with pathogenic Th17 cells in CNS autoimmune models. Furthermore, co-transfer of WT and GKO CD4+ T cells prolonged survival in an IFN-γ dependent manner, although IL-17 transcription was not reduced.

Conclusions

These data demonstrate that IL-17 mediates detrimental clinical consequences in an IFN-γ-deprived environment, independent of extensive neutrophil accumulation or GM-CSF upregulation. The results also suggest that IFN-γ overrides the detrimental IL-17 effector responses via a mechanism downstream of transcriptional regulation.
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Metadata
Title
IFN-γ protects from lethal IL-17 mediated viral encephalomyelitis independent of neutrophils
Authors
Carine Savarin
Stephen A Stohlman
David R Hinton
Richard M Ransohoff
Daniel J Cua
Cornelia C Bergmann
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-104

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