Maternal immune activation in rats blunts brain cytokine and kynurenine pathway responses to a second immune challenge in early adulthood
Maternal immune activation in rats blunts brain cytokine and kynurenine pathway responses to a second immune challenge in early adulthood
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DOI：
10.1016/j.pnpbp.2018.09.011
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发表时间：
2019-03-08
影响因子：
5.6
通讯作者：
Tonelli, Leonardo H.
中科院分区：
文献类型：
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作者：
Clark, Sarah M.;Notarangelo, Francesca M.;Tonelli, Leonardo H.
母体免疫激活（MIA）与病毒模拟聚I：C提供了一个既定的啮齿动物模型研究精神分裂症（SZ）和其他人类神经发育障碍。产后感染是SZ的额外风险因素，并可能累积导致病理生理学的出现。潜在的机制可能涉及色氨酸降解的犬尿氨酸途径（KP）的代谢产物，这很容易由炎症刺激诱导。在这里，我们比较了选定的细胞因子和KP酶的表达，以及选定的KP代谢产物的水平，在MIA后代的大脑后，第二次，急性免疫挑战与脂多糖（LPS）在出生后第35天（青春期）或PND 60（成年早期）。在青春期进行评估，与对照组相比，MIA没有改变促炎细胞因子（TNF-α除外）或KP代谢物水平的表达，但显著降低了抗炎细胞因子IL-4和IL-10的表达，并影响了四种KP酶中两种（IDO 1和TDO 2）的表达。LPS治疗引起促炎和抗炎细胞因子的表达，以及KP酶在MIA后代的明显变化，但没有影响KP代谢物相比，对照组大鼠。在PND 60接受LPS的MIA后代中，这些效应中的一些被钝化。值得注意的是，LPS引起这些动物脑犬尿氨酸水平的显著降低。与SZ相关的假设，这些结果表明，MIA导致越来越多的缺陷，而不是过度活跃，免疫调节脑KP代谢在出生后期间。
Maternal immune activation (MIA) with the viral mimic poly I:C provides an established rodent model for studying schizophrenia (SZ) and other human neurodevelopmental disorders. Postnatal infections are additional risk factors in SZ and may cumulatively contribute to the emergence of pathophysiology. Underlying mechanisms may involve metabolites of the kynurenine pathway (KP) of tryptophan degradation, which is readily induced by inflammatory stimuli. Here we compared the expression of selected cytokines and KP enzymes, and the levels of selected KP metabolites, in the brain of MIA offspring following a second, acute immune challenge with lipopolysaccharides (LPS) on postnatal day (PND) 35 (adolescence) or PND 60 (early adulthood). Assessed in adolescence, MIA did not alter the expression of pro-inflammatory cytokines (except TNF-alpha) or KP metabolite levels compared to controls, but substantially reduced the expression of the anti-inflammatory cytokines IL-4 and IL-10 and influenced the expression of two of the four KP enzymes examined (IDO1 and TDO2). LPS treatment caused distinct changes in the expression of pro- and anti-inflammatory cytokines, as well as KP enzymes in MIA offspring, but had no effect on KP metabolites compared to control rats. Several of these effects were blunted in MIA offspring receiving LPS on PND 60. Notably, LPS caused a significant reduction in brain kynurenine levels in these animals. Of relevance for SZ-related hypotheses, these results indicate that MIA leads to an increasingly defective, rather than an overactive, immune regulation of cerebral KP metabolism during the postnatal period.