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

生命早期 IL-27 表达的调节和代谢影响

• 批准号: 10171779
• 负责人: Cory Michael Robinson
• 金额: $ 7.6万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171779
• 关键词: Address; Adipose tissue; Adult; Bacteria; Biology; Blood; Blood Glucose; Cells; Cessation of life; Child; Choline; DNA Methylation; DNA Methylation Regulation; DNA Sequence; Development; Epigenetic Process; Event; Exhibits; Gene Expression; Genes; Glucose; Human; Hypoglycemia; IL27RA gene; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunologics; Infant Mortality; Infection; Inflammatory Response; Interleukins; Knowledge; Laboratories; Life; Link; Liver; Low Birth Weight Infant; Measures; Metabolic; Methionine; Methylation; Modeling; Mus; Myeloid-derived suppressor cells; Neonatal; Newborn Animals; Newborn Infant; Older Population; Pancreas; Pathway interactions; Peripheral; Phase; Population; Predisposition; Production; Regulation; Reporting; Research; Risk; Risk Factors; Sepsis; Serum; Shapes; Signal Transduction; Skeletal Muscle; Source; Testing; Time; Tissues; Transcript; Translating; Umbilical Cord Blood; Vaccination; Vulnerable Populations; Weight Gain; Work; age group; age related; bisulfite sequencing; blood glucose regulation; cell type; cohort; cytokine; early detection biomarkers; early onset; epigenetic regulation; high risk; immunological intervention; improved; improved outcome; infection risk; macrophage; methyl group; microbial; mortality; mortality risk; mouse model; neonatal human; neonatal mice; neonatal period; neonatal sepsis; neonate; novel; pathogenic bacteria; peripheral blood; pup; systemic inflammatory response; transcriptome; transcriptome sequencing

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.

项目摘要 微生物感染是全世界婴儿死亡的主要原因。对于特别脆弱的人群 如早产儿和低出生体重儿，侵入性感染的风险进一步上升。新生儿 周期是由一个独特的或不成熟的免疫系统定义的，并且许多保护性宿主反应的特征， 与年龄较大的儿童和成人相比，感染率较低。我们的实验室已经鉴定出 免疫抑制细胞因子白细胞介素（IL）-27在人类和小鼠新生儿中升高。其他 最近的研究表明IL-27是早期新生儿败血症的生物标志物。这表明， IL-27可能是一个危险因素，当在细菌挑战期间进一步增加时，会损害宿主 免疫反应我们已经证明，巨噬细胞和髓源性抑制细胞（MDSC）是 新生儿期IL-27升高的主要来源，其作用表现为 血清IL-27与老年人相比。累积起来，这表明IL-27作为宿主分子， 代表免疫干预的目标，以改善宿主反应并降低对感染的易感性 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信号的缺乏转化为 在新生儿败血症期间提高存活率、更好的体重增加和增强的细菌清除。在 根据目前的建议，我们试图了解早期生活中IL-27水平升高的调节和功能性 在感染期间对新生儿造成的后果。深入了解IL-27生物学的这些方面将有助于 为减轻宿主对感染反应中IL-27调节缺陷的靶向方法提供信息。在 我们的第一个目的是探索新生儿IL-27基因低甲基化的假设， 在成年人中通过甲基化降低的表达。在第二个目标中，我们研究了IL-27 有助于葡萄糖稳态的调节。这一假设是从我们的观察得出的。 小鼠脓毒症模型，IL-27受体缺陷新生儿抵抗新生儿期发生低血糖 败血症将在来自野生型和IL-27受体缺陷的新生儿的组织中检查转录组。 在存在和不存在感染的情况下的幼仔。在这个项目完成后，我们预计将有一个 增强对生命早期IL-27差异表达的调控机制的理解 并揭示了宿主免疫力和葡萄糖稳态之间的新联系。这些发现将 转化价值和改善人类新生儿结局的潜力。