A Role for Interferon-Gamma in Focal Cerebral Ischemia in Mice

• Published in: Journal of neuropathology and experimental neurology 2004-09, Vol.63 (9), p.942-955
• Main Authors: LAMBERTSEN, KATE LYKKE, GREGERSEN, RIKKE, MELDGAARD, MICHAEL, CLAUSEN, BETTINA HJELM, HEIBØL, EVA KILDALL, LADEBY, RUNE, KNUDSEN, JENS, FRANDSEN, AASE, OWENS, TREVOR, FINSEN, BENTE
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain Ischemia - genetics; Brain Ischemia - immunology; Brain Ischemia - metabolism; Cerebral Cortex - immunology; Cerebral Cortex - metabolism; Cerebral Cortex - physiopathology; Cerebral Infarction - genetics; Cerebral Infarction - immunology; Cerebral Infarction - metabolism; Disease Models, Animal; Female; Gliosis - genetics; Gliosis - immunology; Gliosis - metabolism; Infarction, Middle Cerebral Artery - genetics; Infarction, Middle Cerebral Artery - immunology; Infarction, Middle Cerebral Artery - metabolism; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - immunology; Macrophages - immunology; Macrophages - metabolism; Male; Medical sciences; Mice; Mice, Knockout; Microglia - immunology; Microglia - metabolism; Nerve Degeneration - genetics; Nerve Degeneration - immunology; Nerve Degeneration - metabolism; Neurology; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/63.9.942

The pro-inflammatory cytokine interferon-gamma (IFNγ) has traditionally been associated with inflammatory CNS disease and more recently with ischemia-induced pathology. Using a murine model of focal cerebral ischemia, we found no evidence for induction of IFNγ mRNA after permanent middle cerebral artery occlusion. In addition, we found that mice deficient in IFNγ or IFNγ receptors developed neocortical infarcts similar in size to those in wild type. In contrast, MBP promoter-IFNγ-transgenic mice consistently developed significantly larger infarcts than non-transgenic mice. Because IFNγ is a potent activator of microglia-macrophages, we investigated the involvement of microglial-macrophage-derived TNF in the larger infarcts. Numbers of TNF mRNA-expressing microglia-macrophages and levels of TNF mRNA and TNF in IFNγ-transgenic and non-transgenic mice were similar. Furthermore, the ischemic brain damage in IFNγ-transgenic mice was unaffected by recombinant soluble TNF receptor I. Taken together, the data argues against a role for IFNγ in cerebral ischemia under normal conditions. However, when present, IFNγ significantly exacerbates ischemia-induced brain damage by mechanisms that appear to be independent of TNF or synergistic neurotoxic interactions of IFNγ and TNF. Irrespective of the mechanism(s) involved, this enhancing effect of IFNγ on ischemia-induced neurotoxicity may need to be considered in diseases where immune IFNγ is involved, such as multiple sclerosis.