A role for interferon-gamma in focal cerebral ischemia in mice

Abstract

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 IFN-γ-transgenic and non-transgenic mice were similar. Furthermore, the ischemic brain damage in IFN-γ-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.