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

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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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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.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Physiology, School of Biomedical Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA

    Hilary A. Seifert, Lisa A. Collier, Cortney B. Chapman & Keith R. Pennypacker

  2. NeuroScience Associates, Knoxville, TN, 37934, USA

    Stanley A. Benkovic

  3. Center for Excellence in Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA

    Alison E. Willing

Authors
  1. Hilary A. Seifert
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  2. Lisa A. Collier
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  3. Cortney B. Chapman
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  4. Stanley A. Benkovic
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  5. Alison E. Willing
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  6. Keith R. Pennypacker
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Correspondence to Keith R. Pennypacker.

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Seifert, H.A., Collier, L.A., Chapman, C.B. et al. Pro-Inflammatory Interferon Gamma Signaling is Directly Associated with Stroke Induced Neurodegeneration. J Neuroimmune Pharmacol 9, 679–689 (2014). https://doi.org/10.1007/s11481-014-9560-2

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  • DOI: https://doi.org/10.1007/s11481-014-9560-2

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