Microglial and peripheral immune priming is partially sexually dimorphic in adolescent mouse offspring exposed to maternal high-fat diet
Microglial and peripheral immune priming is partially sexually dimorphic in adolescent mouse offspring exposed to maternal high-fat diet
复制标题
DOI：
10.1186/s12974-020-01914-1
复制
发表时间：
2020-09-05
影响因子：
9.3
通讯作者：
Tremblay, Marie-Eve
中科院分区：
文献类型：
--
作者：
Bordeleau, Maude;Lacabanne, Chloe;Tremblay, Marie-Eve
背景：母体营养对胎儿正常发育至关重要。虽然在怀孕期间增加营养摄入是必不可少的，但某些营养素的过度消费，如脂肪，可能会对后代造成长期的有害后果。研究母体高脂饮食（mHFD）后果的动物工作揭示了后代中与炎症信号增加相关的母体免疫激活（MIA）表型。这种炎症被认为是引起神经元回路功能障碍的机制之一，特别是在海马中，通过改变脑内驻留的巨噬细胞-小胶质细胞。然而，对炎症和小胶质细胞活动与病理性脑发育之间联系的机制的理解仍然有限。我们假设mHFD诱导的炎症可以通过改变它们的特异性基因表达特征、群体密度和/或功能来引发小胶质细胞。多重ELISA，rt-qPCR）和细胞（即，组织化学、电子显微镜）技术来研究mHFD（饱和和不饱和脂肪）相对于对照饮食对小鼠中的炎性引发以及小胶质细胞转录组特征、密度、分布、形态和超微结构的影响。这些分析是在出生后30天对母亲和/或其青春期后代进行的。结果：我们的研究表明，mHFD导致MIA，其定义为母亲循环中白细胞介素（IL）-6水平升高。这种表型与mHFD暴露的两种性别后代对外周脂多糖的炎症反应加剧相关。小胶质细胞的形态也发生了变化，有增加的小胶质细胞与星形胶质细胞在海马CA1的mHFD暴露的雄性后代，以及减少小胶质细胞相关的细胞外空间口袋在同一地区的mHFD暴露的后代的两种性别。一个减少的mRNA表达的炎症调节mHFD暴露的后代，特别是在mHFD暴露的后代海马Tgfb1和小胶质细胞受体Tmem119，Trem2，和Cx3cr1另外测量：结论：在这里，我们描述了如何在怀孕期间的饮食习惯和养育，特别是丰富的脂肪饮食的消费，可以影响外周免疫引发的后代。我们还发现，小胶质细胞的基因表达特征，形态和与海马实质的相互作用，在一个部分性二态的方式，这可能有助于对后代的不良神经发育结果的影响。
Background: Maternal nutrition is critical for proper fetal development. While increased nutrient intake is essential during pregnancy, an excessive consumption of certain nutrients, like fat, can lead to long-lasting detrimental consequences on the offspring. Animal work investigating the consequences of maternal high-fat diet (mHFD) revealed in the offspring a maternal immune activation (MIA) phenotype associated with increased inflammatory signals. This inflammation was proposed as one of the mechanisms causing neuronal circuit dysfunction, notably in the hippocampus, by altering the brain-resident macrophages-microglia. However, the understanding of mechanisms linking inflammation and microglial activities to pathological brain development remains limited. We hypothesized that mHFD-induced inflammation could prime microglia by altering their specific gene expression signature, population density, and/or functions.Methods: We used an integrative approach combining molecular (i.e., multiplex-ELISA, rt-qPCR) and cellular (i.e., histochemistry, electron microscopy) techniques to investigate the effects of mHFD (saturated and unsaturated fats) vs control diet on inflammatory priming, as well as microglial transcriptomic signature, density, distribution, morphology, and ultrastructure in mice. These analyses were performed on the mothers and/or their adolescent offspring at postnatal day 30.Results: Our study revealed that mHFD results in MIA defined by increased circulating levels of interleukin (IL)-6 in the mothers. This phenotype was associated with an exacerbated inflammatory response to peripheral lipopolysaccharide in mHFD-exposed offspring of both sexes. Microglial morphology was also altered, and there were increased microglial interactions with astrocytes in the hippocampus CA1 of mHFD-exposed male offspring, as well as decreased microglia-associated extracellular space pockets in the same region of mHFD-exposed offspring of the two sexes. A decreased mRNA expression of the inflammatory-regulating cytokineTgfb1and microglial receptors Tmem119, Trem2, and Cx3cr1 was additionally measured in the hippocampus of mHFD-exposed offspring, especially in males.Conclusions: Here, we described how dietary habits during pregnancy and nurturing, particularly the consumption of an enriched fat diet, can influence peripheral immune priming in the offspring. We also found that microglia are affected in terms of gene expression signature, morphology, and interactions with the hippocampal parenchyma, in a partially sexually dimorphic manner, which may contribute to the adverse neurodevelopmental outcomes on the offspring.