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

Abstract

Background Systemic 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. Methods Mice 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. Results Repeated 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. Conclusions These 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.

Deciphering the mechanism underlying late-onset Alzheimer disease

“…67 Moreover, chronic or repeated systemic inflamma tion in mice primes microglia to induce an exaggerated proinflammatory response to subsequent stimulations. 68 Consistent with these findings, microarray data from aged human and murine brain tissue point to increased transcriptional activity of genes related to cellular stress and inflammation in the course of ageing, 10,69,70 a state that has been termed 'inflammaging' . 71 Hence, the observation that sickness behaviour at young age is relatively benign, whereas systemic inflammation in the elderly can lead to delirium, 72 could be explained by an ageassociated priming of microglia.…”

DNGR-1+dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain

“…5), and those that were present were situated in contact with blood vessels (Fig. 5A) (Greter et al, 2005;Lv et al, 2011;Prodinger et al, 2011;Puntener et al, 2012). Further combined analysis by FC and IF with an array of different cellular markers will shed new light on the phenotype, activation stage and role of brain myeloid cells in the response to diverse neuroinflammatory stimuli.…”

Connection Between Periodontitis and Alzheimer’s Disease: Possible Roles of Microglia and Leptomeningeal Cells

“…Repeated LPS-induced chronic systemic inflammation in mice resulted in prolonged IL-1b production, as well as microglial activation in the brain (15). The mice that received a systemic inflammatory challenge in late gestation were predisposed to develop AD-like neuropathology during the course of aging.…”