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Published on: May 2, 2018
Central and peripheral immune responses to low-dose lipopolysaccharide in a mouse model of the 15q13.3 microdeletion
Amal A Halawa1, Katherine A Rees2, Kristin M McCamy2
1Department of Neuroscience & Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.
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 2 MB 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) α7, 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) (100 μg/kg) in adult heterozygous (Het) and wildtype (WT) mice. Serum levels of inflammatory markers were measured 2 h 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-1β), tumor necrosis factor alpha (TNF-α), IL-6 and IL-10, but not interferon-γ. There was no effect of genotype but a sexual dimorphic response for TNF-α, with females exhibiting greater LPS-induced TNF-α 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-1β, IL-6, and TNF-α compared to saline controls, with no effect of genotype, but a significant sex-effect was detected for IL-1β. 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.
Insights
The 15q13.3 microdeletion did not alter innate immune responses to lipopolysaccharide (LPS) in mice. However, sex differences were observed in inflammatory responses, with females showing higher TNF-α levels.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- The human 15q13.3 microdeletion (MD) is linked to variable neuropathological outcomes, suggesting genetic and non-genetic factor interplay.
- The 15q13.3 MD region includes genes like CHRNA7 and KLF13, involved in immune regulation.
- Understanding immune responses in MD carriers is crucial for predicting clinical severity.
Purpose of the Study:
- To investigate the impact of heterozygous 15q13.3 microdeletion on peripheral and central innate immune responses.
- To assess the effects of a lipopolysaccharide (LPS) challenge on inflammatory markers in a mouse model.
- To identify potential sex-specific differences in immune responses.
Main Methods:
- A mouse model (Df[h15q13]/+) with heterozygous deletion of the 15q13.3 region was used.
- Mice received an intraperitoneal injection of LPS (100 μg/kg) or saline.
- Serum inflammatory markers (cytokines) and hippocampal mRNA expression were measured using multiplex assays and qPCR.
Main Results:
- LPS significantly increased serum levels of IL-1β, TNF-α, IL-6, and IL-10, but not IFN-γ.
- No significant effect of genotype on cytokine levels or central c-fos expression was observed.
- Sexually dimorphic responses were noted: females had higher LPS-induced TNF-α, and a sex-effect was detected for IL-1β mRNA.
Conclusions:
- Heterozygous 15q13.3 microdeletion did not alter innate immune responses to a low-dose LPS challenge in mice.
- Sex-specific differences in inflammatory responses were observed, highlighting the role of sex in immune modulation.
- Further research is needed to elucidate the complex interplay of genetics, environment, and sex in neurodevelopmental disorders.
