Pro-Inflammatory Interferon Gamma Signaling is Directly Associated with Stroke Induced Neurodegeneration

Hilary A. Seifert; Lisa A. Collier; Cortney B. Chapman; Stanley A. Benkovic; Alison E. Willing; Keith R. Pennypacker

doi:10.1007/s11481-014-9560-2

Pro-Inflammatory Interferon Gamma Signaling is Directly Associated with Stroke Induced Neurodegeneration

Hilary A. Seifert
, Lisa A. Collier
, Cortney B. Chapman
, Stanley A. Benkovic
, Alison E. Willing
, Keith R. Pennypacker

Research output: Contribution to journal › Article › peer-review

97 Scopus citations

Abstract

The delayed immune response to stroke is responsible for the increased neural injury that continues to occur after the initial ischemic event. This delayed immune response has been linked to the spleen, as splenectomy prior to middle cerebral artery occlusion (MCAO) is neuroprotective. Interferon gamma (IFNγ) is linked to the splenic response, which enhances neural injury following MCAO. IFNγ activates the expression of the inflammatory chemokine interferon-inducible protein 10 (IP-10). This study was designed to determine the role of IFNγ signaling in the inflammatory response following MCAO. Expression of IP-10 increased in the brain and the spleen following MCAO. Splenectomy inhibited the increase of IP-10 in the brain post-MCAO, while recombinant IFNγ administration to splenectomized rats returned IP-10 levels in the brain to levels found in rats after MCAO only. Systemic administration of an IFNγ neutralizing antibody to MCAO-treated rats reduced infarct volume and IP-10 levels in the brain. T cell infiltration was reduced in the MCAO-damaged brains of IFNγ antibody-treated animals relative to those that received isotype control antibodies. Additionally, inhibiting IFNγ signaling with splenectomy or an IFNγ neutralizing antibody blocked the induction of IP-10 expression and decreased neurodegeneration following MCAO. Targeting this pro-inflammatory pathway following stroke could be a promising stroke therapeutic.

Original language	English
Pages (from-to)	679-689
Number of pages	11
Journal	Journal of NeuroImmune Pharmacology
Volume	9
Issue number	5
DOIs	https://doi.org/10.1007/s11481-014-9560-2
State	Published - Oct 24 2014

Bibliographical note

Publisher Copyright:
© 2014, Springer Science+Business Media New York.

Funding

Acknowledgments The authors would like to thank the Lisa Muma Weitz Laboratory for Advanced Microscopy & Cell Imaging at the University of South Florida for assistance with obtaining the confocal images. This research was funded by National Institutes of Health – Neurological Disease and Stroke 1-R01-NS052839.

Funders	Funder number
National Institutes of Health/National Institute of Neurological Disease and Stroke FIRST	1-R01-NS052839
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke	R21NS078517

Keywords

Chemokines
IP-10
Lymphocytes
Monocytes
Spleen

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Immunology and Allergy
Immunology
Pharmacology

Access to Document

10.1007/s11481-014-9560-2

Cite this

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title = "Pro-Inflammatory Interferon Gamma Signaling is Directly Associated with Stroke Induced Neurodegeneration",

abstract = "The delayed immune response to stroke is responsible for the increased neural injury that continues to occur after the initial ischemic event. This delayed immune response has been linked to the spleen, as splenectomy prior to middle cerebral artery occlusion (MCAO) is neuroprotective. Interferon gamma (IFNγ) is linked to the splenic response, which enhances neural injury following MCAO. IFNγ activates the expression of the inflammatory chemokine interferon-inducible protein 10 (IP-10). This study was designed to determine the role of IFNγ signaling in the inflammatory response following MCAO. Expression of IP-10 increased in the brain and the spleen following MCAO. Splenectomy inhibited the increase of IP-10 in the brain post-MCAO, while recombinant IFNγ administration to splenectomized rats returned IP-10 levels in the brain to levels found in rats after MCAO only. Systemic administration of an IFNγ neutralizing antibody to MCAO-treated rats reduced infarct volume and IP-10 levels in the brain. T cell infiltration was reduced in the MCAO-damaged brains of IFNγ antibody-treated animals relative to those that received isotype control antibodies. Additionally, inhibiting IFNγ signaling with splenectomy or an IFNγ neutralizing antibody blocked the induction of IP-10 expression and decreased neurodegeneration following MCAO. Targeting this pro-inflammatory pathway following stroke could be a promising stroke therapeutic.",

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AU - Willing, Alison E.

AU - Pennypacker, Keith R.

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Pro-Inflammatory Interferon Gamma Signaling is Directly Associated with Stroke Induced Neurodegeneration

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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