The effects of ageing on microglial phenotypes and the central nervous system response to systemic inflammation

Abstract

Microglial cells are resident immune cells of the central nervous system (CNS) that participate in the CNS response to systemic inflammation by producing inflammatory mediators, which subsequently contribute to the behavioural and metabolic adaptations to systemic infections collectively termed sickness behaviour. Ageing leads to changes in microglial phenotype and a maladaptive, exaggerated CNS inflammatory and behavioural response to systemic infection has been described in aged rodents, which could have a negative impact on CNS health. However, most studies examining the effects of ageing on microglia have focused on a single region of the brain (the hippocampus) and have used a single model of infection, the bacterial mimetic lipopolysaccharide (LPS). This raises two important questions – are microglia in different parts of the brain equally effected by ageing, and do different models of systemic infections have different effects on sickness behaviour and on microglia? To address these questions we used immunohistochemistry, quantitative PCR and behavioural assays to investigate the effects of region on age related changes in microglial phenotype along a rostral to caudal axis and the CNS inflammatory and behavioural response elicited by LPS was compared to that elicited during a live infection with Salmonella typhimurium. We detected significant differences in the effects of ageing on microglia of different regions of the CNS, with microglia of white matter areas and the cerebellum demonstrating significantly greater changes in expression of activation markers than those of rostral grey matter areas. Co-ordination and balance was impaired in aged mice at baseline and some sickness behaviours were exaggerated in aged mice in response to LPS injection, whereas Salmonella typhimurium infection induced long-lasting reductions in exploratory activity of equal size in young and aged mice and, in aged mice, co-ordination and balance deficits and prolonged weight loss. A low grade, prolonged inflammatory response was detected in the hippocampus which was accompanied by increased expression of microglial activation markers throughout the young and aged CNS, particularly in the spinal cord, where increased axonal stress and changes in the organisation of the paranodal junction were also observed. These changes in cytokine levels and microglial phenotype were mostly of similar magnitude in young and aged mice, contrasting to the effects of LPS. These results highlight regional differences in the sensitivity of microglia to systemic infection and ageing and show extensive differences between the effects of the bacterial mimetic LPS and a live bacterial infection on microglia and on sickness behaviour in young and aged mice. They also have important implications for the study of ageing microglia regarding the selection of the infection models and in deciding which CNS regions to examine.

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ORCID for Jessica L. Teeling: orcid.org/0000-0003-4004-7391

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