IFN-gamma signaling in the central nervous system controls the course of experimental autoimmune encephalomyelitis independently of the localization and composition of inflammatory foci

Journal of Neuroinflammation

Athena M Soulika³  David Pleasure²  Sarah Chanamara¹  Eunyoung Lee³ 

[1] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California, USA, 95817;The Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, USA, 95817;Department of Dermatology, School of Medicine, University of California, Davis Sacramento, California, USA, 95816

关键词: inflammation;    STAT1;    IFNγ;    EAE;    brainstem;    cerebellum;    microglia;   

Others  :  1212882
DOI  :  10.1186/1742-2094-9-7

 received in 2011-07-16, accepted in 2012-01-16,  发布年份 2012

【 摘 要 】

Background

Murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFNγ) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. However, the exact mechanism by which IFNγ signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive.

Methods

We induced EAE in IFNγ-/- mice and bone marrow chimeric mice in which IFNγR is not expressed in the CNS but is intact in the periphery (IFNγR^CNSKO) and vice versa (IFNγR^periKO). Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset. Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry. CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration.

Results

Incidence and severity of atypical EAE were more pronounced in IFNγR^CNSKO as compared to IFNγR^periKO mice. Contrary to what we anticipated, cerebella/brainstems of IFNγR^CNSKO mice were only minimally infiltrated, while the same areas of IFNγR^periKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFNγR^periKO mice was characterized by persistent neutrophil-rich foci as compared to IFNγR^CNSKO. Immunohistochemical analysis of the CNS of IFNγ-/- and IFNγR chimeric mice revealed that IFNγ protective actions are exerted through microglial STAT1.

Conclusions

Alterations in distribution and composition of CNS inflammatory foci are not sufficient for the onset of atypical EAE. IFNγ dictates the course of neuroinflammatory disorders mainly through actions exerted within the CNS. This study provides strong evidence that link microglial STAT1 inactivation to vestibular dysfunction.

【 授权许可】

   
2012 Lee et al; licensee BioMed Central Ltd.

【 图 表 】

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