Osborne Brittany F, Turano Alexandra, Caulfield Jasmine I, Schwarz Jaclyn M
University of Delaware, Department of Psychological and Brain Sciences, 108 Wolf Hall, Newark, DE, 19716, USA.
Neurosci Lett. 2019 Jan 23;692:1-9. doi: 10.1016/j.neulet.2018.10.044. Epub 2018 Oct 24.
Early-life infection has been shown to have profound effects on the brain and behavior across the lifespan, a phenomenon termed "early-life programming". Indeed, many neuropsychiatric disorders begin or have their origins early in life and have been linked to early-life immune activation (e.g. autism, ADHD, and schizophrenia). Furthermore, many of these disorders show a robust sex bias, with males having a higher risk of developing early-onset neurodevelopmental disorders. The concept of early-life programming is now well established, however, it is still unclear how such effects are initiated and then maintained across time to produce such a phenomenon. To begin to address this question, we examined changes in microglia, the immune cells of the brain, and peripheral immune cells in the hours immediately following early-life infection in male and female rats. We found that males showed a significant decrease in BDNF expression and females showed a significant increase in IL-6 expression in the cerebellum following E.coli infection on postnatal day 4; however, for most cytokines examined in the brain and in the periphery we were unable to identify any sex differences in the immune response, at least at the time points examined. Instead, neonatal infection with E.coli increased the expression of a number of cytokines in the brain of both males and females similarly including TNF-α, IL-1β, and CD11b (a marker of microglia activation) in the hippocampus and, in the spleen, TNF-α and IL-1β. We also found that protein levels of GRO-KC, MIP-1a, MCP1, IP-10, TNF-α, and IL-10 were elevated 8-hours postinfection, but this response was resolved by 24-hours. Lastly, we found that males have more thin microglia than females on P5, however, neonatal infection had no effect on any of the microglia morphologies we examined. These data show that sex differences in the acute immune response to neonatal infection are likely gene, region, and even time dependent. Future research should consider these factors in order to develop a comprehensive understanding of the immune response in males and females as these changes are likely the initiating agents that lead to the long-term, and often sex-specific, effects of early-life infection.
早期感染已被证明会对个体一生的大脑和行为产生深远影响，这一现象被称为“早期编程”。事实上，许多神经精神疾病在生命早期就开始出现或起源于此，并与早期免疫激活有关（如自闭症、注意力缺陷多动障碍和精神分裂症）。此外，这些疾病中的许多都表现出明显的性别差异，男性患早发性神经发育障碍的风险更高。早期编程的概念现已确立，然而，目前尚不清楚这种影响是如何启动并随时间维持从而产生这一现象的。为了开始解决这个问题，我们研究了雄性和雌性大鼠在早期感染后数小时内大脑中的免疫细胞——小胶质细胞以及外周免疫细胞的变化。我们发现，在出生后第4天感染大肠杆菌后，雄性大鼠小脑内脑源性神经营养因子（BDNF）表达显著降低，而雌性大鼠小脑内白细胞介素-6（IL-6）表达显著增加；然而，对于在大脑和外周检测的大多数细胞因子，至少在所检测的时间点，我们未能发现免疫反应存在任何性别差异。相反，大肠杆菌的新生儿感染同样增加了雄性和雌性大鼠大脑中多种细胞因子的表达，包括海马体中的肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和小胶质细胞激活标志物CD11b，以及脾脏中的TNF-α和IL-1β。我们还发现，感染后8小时，生长调节致癌基因-α（GRO-KC）、巨噬细胞炎性蛋白-1α（MIP-1a）、单核细胞趋化蛋白-1（MCP1）、干扰素诱导蛋白10（IP-10）、TNF-α和IL-10的蛋白质水平升高，但这种反应在24小时后消失。最后，我们发现出生后第5天雄性大鼠的细小微胶质细胞比雌性大鼠多，然而，新生儿感染对我们检测的任何小胶质细胞形态均无影响。这些数据表明，新生儿感染急性免疫反应中的性别差异可能取决于基因、区域，甚至时间。未来的研究应考虑这些因素，以便全面了解雄性和雌性的免疫反应，因为这些变化可能是导致早期感染产生长期且通常具有性别特异性影响的起始因素。
