The regulation of early life interleukin-27 expression and metabolic impact

项目总结 微生物感染是全球婴儿死亡的主要原因。针对特别易受伤害的人群 例如早产儿和低出生体重儿，侵袭性感染的风险进一步升级。新生儿 时期是由不同的或不成熟的免疫系统和保护性宿主对 与年龄较大的儿童和成年人相比，感染不足。我们的实验室已经确认了这种表达 在免疫抑制细胞因子中，白介素27在人类和小鼠新生儿中升高。其他 最近的研究表明，IL-27是早发性新生儿败血症的生物标志物。这表明升高的 IL-27可能是一个危险因素，当在细菌攻击期间进一步升高时，会损害宿主 免疫反应。我们已经证明，巨噬细胞和髓系抑制细胞(MDSCs)是 新生儿期IL-27升高的主要来源及其贡献表现为血浆IL-27水平升高 血清IL-27水平与老年人群比较。总体而言，这表明IL-27是一种宿主分子， 代表免疫干预的目标，以改善宿主的反应并降低感染的易感性。 在生命的早期。我们在小鼠模型中提供了强有力的证据，表明IL-27信号的缺失可以转化为 在新生儿败血症期间，提高存活率、体重增加和细菌清除。在 目前的建议，我们试图了解调节早期生命中IL-27水平升高的功能 感染期间对新生儿的影响。更深入地了解IL-27生物学的这些方面将有所帮助 提供有针对性的方法，以减轻宿主对感染反应中IL-27调节的缺陷。在 首先，我们探索了新生儿IL-27基因低甲基化的假设，允许增加 由于甲基化而在成人体内减少的表达。在第二个目标中，我们调查了IL-27的假设 有助于调节葡萄糖的动态平衡。这一假说是从我们的观察中得出的 IL-27受体缺陷新生儿抵抗新生儿低血糖的小鼠败血症模型 败血症。转录组将在野生型和IL-27受体缺陷新生儿的组织中进行检测。 幼崽在存在和没有感染的情况下。在这个项目完成后，我们预计将有一个 加强对生命早期导致IL-27差异表达的调节机制的理解 并发现了宿主免疫和葡萄糖动态平衡之间的新联系。这些发现将会有 翻译价值和改善人类新生儿结局的潜力。

PROJECT SUMMARY Microbial infections are a major cause of infant mortality worldwide. For particularly vulnerable populations such as pre-term and low birth weight babies, the risk of invasive infections further escalates. The neonatal period is defined by a distinct or immature immune system, and many features of a protective host response to infection are deficient as compared with older children and adults. Our laboratory has identified that expression of the immune suppressive cytokine interleukin (IL)-27 is elevated in human and murine neonates. Other recent studies have shown IL-27 to be a biomarker for early onset neonatal sepsis. This suggests that elevated IL-27 may represent a risk factor and when further increased during bacterial challenge, compromise the host immune response. We have shown that macrophages and myeloid-derived suppressor cells (MDSCs) are the dominant sources of elevated IL-27 in the neonatal phase and their contributions manifest as elevated levels of serum IL-27 compared with older populations. Cumulatively, this points to IL-27 as a host molecule that represents a target for immune intervention to improve the host response and reduce susceptibility to infection early in life. We present strong evidence in a mouse model that the absence of IL-27 signaling translates to improved survival, better weight gain, and enhanced clearance of bacteria during neonatal sepsis. In the current proposal, we seek to understand the regulation of elevated levels of early life IL-27 and the functional consequence to neonates during infection. A deeper understanding of these aspects of IL-27 biology will help to inform targeted approaches to mitigate IL-27-regulated deficiencies in the host response to infection. In the first aim we explore the hypothesis that IL-27 genes are hypomethylated in neonates allowing for increased expression that is reduced in adults by methylation. In the second aim we investigate the hypothesis that IL-27 contributes to the regulation of glucose homeostasis. This hypothesis is derived from the observation in our murine sepsis model, that IL-27 receptor-deficient neonates resist hypoglycemia that develops during neonatal sepsis. The transcriptome will be examined in tissues from wild-type and IL-27 receptor-deficient neonatal pups in the presence and absence of infection. At the completion of this project, we expect to have an enhanced understanding of regulatory mechanisms that contribute to differential IL-27 expression early in life and uncovered a novel link between host immunity and glucose homeostasis. These findings will have translational value and the potential to improve outcomes in human neonates.