Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia

Ursula Püntener,Jessica L Teeling,Steven G Booth,V Hugh Perry

doi:10.1186/1742-2094-9-146

Abstract

BackgroundSystemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against overactivity of the immune system. In this study, we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection.MethodsMice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry. To assess priming of the innate immune response in the brain, mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral intracerebral injection of LPS.ResultsRepeated systemic LPS challenges resulted in increased brain IL-1β, TNF-α and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1β and IL-12 levels in Salmonella typhimurium-infected mice increased over three weeks, with high interferon-γ levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS four weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice.ConclusionsThese studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have a profound effect on the onset and/or progression of pre-existing neurodegenerative disease.

Highlights

Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes
Others, have shown that microglia become primed by ongoing neuropathology in the brain, which increases their response towards subsequent inflammatory stimuli, including systemic inflammation [12,13] Similar findings have been made in aged rodents [14,15], where it has been shown that there is an exaggerated behavioural and innate immune response in the brain to systemic bacterial and viral infections, but the molecular mechanisms underlying the microglial priming under these conditions is far from understood
The first LPS challenge led to an increase in protein levels of interferon-gamma (IFN-γ), interleukin-1 beta (IL-1β) and IL-12 in the serum (Figure 1A, IFN-γ 7.1-fold P < 0.001, IL-1β 20-fold P < 0.001, IL-12 1.6-fold not significant (n.s.)) and the spleen (Figure 1B, IFN-γ 11.5-fold P < 0.001, IL-1β 18-fold P < 0.001, IL-12 5.8-fold P < 0.001)

Summary

Introduction

Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. The communication pathways from the site of inflammation to the brain have been investigated in animal models and systemic challenge with lipopolysaccharide (LPS) or double-stranded RNA (poly I:C) have been widely used to mimic aspects of bacterial and viral infection respectively [3,4]. These studies have provided evidence that systemically generated inflammatory mediators signal to the brain via both neural and humoral routes, the latter signalling via the circumventricular organs or across the blood brain barrier (BBB). Others, have shown that microglia become primed by ongoing neuropathology in the brain, which increases their response towards subsequent inflammatory stimuli, including systemic inflammation [12,13] Similar findings have been made in aged rodents [14,15], where it has been shown that there is an exaggerated behavioural and innate immune response in the brain to systemic bacterial and viral infections, but the molecular mechanisms underlying the microglial priming under these conditions is far from understood

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Discussion

Conclusion