36. Immune adaptation in the central nervous system in response to systemic infection

Abstract

Introduction: Acute systemic inflammation leads to production of inflammatory mediators and transient metabolic and behavioural changes. In models of chronic neurodegeneration this acute inflammation can cause neuronal damage through activation of ‘primed’ microglia. Here, we investigated innate immune activation in the healthy and diseased CNS in response to chronic systemic bacterial infection. Methods: Mice received a sublethal dose (10 × 6 pfu) of life Salmonella typhimurium. Serum, spleen and brain cytokines were measured at various time points and microglia and endothelial cell phenotypes studied by immunohistochemistry. The ME7 prion model was used to study the effect of systemic inflammation on ongoing neurodegeneration. Results: Peripheral cytokines (IFNg, IL-1b, IL-12) peaked at day 7 while brain cytokine levels (IL-1b, IL-12) continued to increase in S. typhimurium infected mice up to 21 days. Transient changes in CD11b and CD68 expression on microglial cells were observed but persistent MHCII expression on cerebral endothelial cells was detected up to 8 weeks after infection. Mice with ME7 prion disease showed exaggerated activation of microglia following systemic infection and a significant increase in CD3+ cells in brain regions with ongoing neurodegeneration. Conclusion: These studies reveal significant phenotype changes in microglia and cerebral blood vessels of naı¨ve mice in response to systemic infection, suggesting ‘priming’ of microglial and/or endothelial cells. These changes may have a profound effect on pre-existing neurodegenerative disease.