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Gene Expression Regulation in Brain Underlying Innate Immune Memory

ABSTRACT: As the brain’s resident immune cells, microglia upregulate inflammatory gene expression to promote immune functions. Following the response to early life infection, microglia can remain in a “primed” state in which a subsequent immune trigger produces a hyper-activation. Paradoxically, multiple repeated immune activating events can lead to tolerance, the suppression of immune gene expression and function. Both priming and tolerance represent a form of cellular memory that may be disrupted in neurodevelopmental disorders and is largely unexplored in microglia. We hypothesize that acute versus repeated immune activation engages expression of distinct sets of genes, leading to either microglial priming or tolerance. Using in vivo peripheral injections of low dose liposaccharide (LPS 500ug/kg intraperitoneal) to mimic bacterial infection in mice, we compared animals recievig 1, 2, 3, or 4 daily doses of LPS compared to Vehicle (PBS) controls. We examined tissue from three brain regions, the hippocampus, striatum and frotal cortex by RNAseq.

ORGANISM(S): Mus musculus

PROVIDER: GSE165287 | GEO | 2024/09/25

REPOSITORIES: GEO

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Project description:Acute cognitive impairment (i.e., delirium) is common in elderly emergency department patients and frequently results from infections that are unrelated to the central nervous system. Since activation of the peripheral innate immune system induces brain microglia to produce inflammatory cytokines that are responsible for behavioral deficits, we investigated if aging exacerbated neuroinflammation and sickness behavior after peripheral injection of lipopolysaccharide (LPS). Microarray analysis revealed a transcriptional profile indicating the presence of primed or activated microglia and increased inflammation in the aged brain. Furthermore, aged mice had a unique gene expression profile in the brain after an intraperitoneal injection of LPS, and the LPS-induced elevation in the brain inflammatory cytokines and oxidative stress was both exaggerated and prolonged compared with adults. Aged mice were anorectic longer and lost more weight than adults after peripheral LPS administration. Moreover, reductions in both locomotor and social behavior remained 24 h later in aged mice, when adults had fully recovered, and the exaggerated neuroinflammatory response in aged mice was not reliably paralleled by increased circulating cytokines in the periphery. Taken together these data establish that activation of the peripheral innate immune system leads to exacerbated neuroinflammation in the aged as compared with adult mice. This dysregulated link between the peripheral and central innate immune system is likely to be involved in the severe behavioral deficits that frequently occur in older adults with systemic infections. Experiment Overall Design: In this study, adult and aged mice were injected intraperitoneal with sterile saline or Escherichia coli LPS (0.33 mg/kg, ~10 µg/mouse; serotype 0127:B8, Sigma). This dosage of LPS was used because it induces a mild transient sickness behavior in young adults. Mice were killed 4 h after saline or LPS injection by CO2 asphyxiation. Blood samples were collected and brains were removed, separated in half at the longitudinal fissure, frozen in liquid nitrogen, and stored (-80°C) until assaying. Total RNA was later isolated from some brain samples for microarray analysis (n=3).

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Gene Expression Regulation in Brain Underlying Innate Immune Memory

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