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

Journal of Neuroinflammation

Cornelia C Bergmann²  Daniel J Cua¹  Richard M Ransohoff²  David R Hinton³  Stephen A Stohlman²  Carine Savarin² 

[1] Merck Research Laboratories, DNAX Discovery Research, 901 California Ave, Palo Alto, CA, 94304, USA;Department of Neurosciences NC30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA;Department of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA, 90033, USA

关键词: Neurotropic coronavirus;    Neutrophils;    IL-17;    IFN-γ;    CD4⁺ T cells;    Encephalomyelitis;    Central nervous system;   

Others  :  1212585
DOI  :  10.1186/1742-2094-9-104

 received in 2012-03-07, accepted in 2012-04-10,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Savarin et al.; licensee BioMed Central Ltd.

【 图 表 】

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