Dataset Information

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

ABSTRACT:

Background

Murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFN?) 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 IFN? 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 IFN?-/- mice and bone marrow chimeric mice in which IFN?R is not expressed in the CNS but is intact in the periphery (IFN?RCNSKO) and vice versa (IFN?RperiKO). 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 IFN?RCNSKO as compared to IFN?RperiKO mice. Contrary to what we anticipated, cerebella/brainstems of IFN?RCNSKO mice were only minimally infiltrated, while the same areas of IFN?RperiKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFN?RperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFN?RCNSKO. Immunohistochemical analysis of the CNS of IFN?-/- and IFN?R chimeric mice revealed that IFN? 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. IFN? 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.

SUBMITTER: Lee E

PROVIDER: S-EPMC3293042 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Lee Eunyoung E Chanamara Sarah S Pleasure David D Soulika Athena M AM

Journal of neuroinflammation 20120116

<h4>Background</h4>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 immu ...[more]

PMID: 22248039

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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