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

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 (IFN gamma) is linked to the splenic response, which enhances neural injury following MCAO. IFN gamma activates the expression of the inflammatory chemokine interferon-inducible protein 10 (IP-10). This study was designed to determine the role of IFN gamma 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 IFN gamma administration to splenectomized rats returned IP-10 levels in the brain to levels found in rats after MCAO only. Systemic administration of an IFN gamma 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 IFN gamma antibody-treated animals relative to those that received isotype control antibodies. Additionally, inhibiting IFN gamma signaling with splenectomy or an IFN gamma 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.