Central and peripheral immune responses to low-dose lipopolysaccharide in a mouse model of the 15q13.3 microdeletion.
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abstract
Carriers of the human 15q13.3 microdeletion (MD) present with a variable spectrum of neuropathological phenotypes that range from asymptomatic to severe clinical outcomes, suggesting an interplay of genetic and non-genetic factors. The most common 2MB 15q13.3 MD encompasses six genes (MTMR10, FAN1, TRPM1, KLF13, OTUD7A, and CHRNA7), which are expressed in neuronal and non-neuronal tissues. The nicotinic acetylcholine receptor (nAChR) 7, encoded by CHRNA7, is a key player in the cholinergic anti-inflammatory pathway, and the transcription factor KLF13 is also involved in immune responses. Using a mouse model with a heterozygous deletion of the orthologous region of the human 15q13.3 (Df[h15q13]/+), the present study examined peripheral and central innate immune responses to an acute intraperitoneal (i.p.) injection of the bacteriomimetic, lipopolysaccharide (LPS) (100g/kg) in adult heterozygous (Het) and wildtype (WT) mice. Serum levels of inflammatory markers were measured 2h post injection using a Multiplex assay. In control saline injected animals, all measured cytokines were at or below detection limits, whereas LPS significantly increased serum levels of interleukin 1beta (IL-1), tumor necrosis factor alpha (TNF-), IL-6 and IL-10, but not interferon-. There was no effect of genotype but a sexual dimorphic response for TNF-, with females exhibiting greater LPS-induced TNF- serum levels than males. In situ hybridization revealed similar increases in LPS-induced c-fos mRNA expression in the dorsal vagal complex in all groups. The hippocampal expression of the pro-inflammatory cytokines was evaluated by real-time quantitative PCR. LPS-treatment resulted in significantly increased mRNA expression for IL-1, IL-6, and TNF- compared to saline controls, with no effect of genotype, but a significant sex-effect was detected for IL-1. The present study provided no evidence for interactive effects between the heterozygous 15q13.3 MD and a low-dose LPS immune challenge in innate peripheral or central immune responses, although, sex-differential effects in males and females were detected.
