Regulation of Intestinal Immunity by Aryl Hydrocarbon Receptor Signaling in Necrotizing Enterocolitis

坏死性小肠结肠炎中芳基烃受体信号传导对肠道免疫的调节

• 批准号: 10311910
• 负责人: Lila Nolan
• 金额: $ 7.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311910
• 关键词: Adaptive Immune System; Address; Adult; Affect; Anti-Inflammatory Agents; Architecture; Aryl Hydrocarbon Receptor; Attenuated; Catabolism; Cells; Colitis; Complex; Cytometry; Data; Dendritic Cells; Dendritic cell activation; Development; Diet; Dioxygenases; Disease; Distal part of ileum; Enteral; Enzymes; Epithelial; Epithelial Cells; Excision; Flow Cytometry; Functional disorder; Gastrointestinal Diseases; Genes; Homeostasis; Human; ITGAX gene; Immune; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Indole-3-Carbinol; Infant; Inflammation; Inflammatory; Inflammatory Response; Intake; Interleukin-1 beta; Intestines; Knock-out; Knowledge; Kynurenine; Lamina Propria; Ligands; Mediating; Morbidity - disease rate; Mucous Membrane; Mus; Necrosis; Necrotizing Enterocolitis; Neonatal Intensive Care Units; Nutritional; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Physiological; Pomegranate; Population; Premature Infant; Prevention strategy; Proteins; Receptor Activation; Receptor Cell; Receptor Signaling; Regulation; Research; Resected; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Small Intestines; Supplementation; Testing; Therapeutic; Tight Junctions; Tissues; Tryptophan; Tumor-infiltrating immune cells; Wild Type Mouse; Work; aryl hydrocarbon receptor ligand; attenuation; cell type; chemokine; cruciferous vegetable; cytokine; dietary; dysbiosis; experience; gut microbiota; indoleamine; inflammatory disease of the intestine; insight; intestinal barrier; intestinal epithelium; intestinal homeostasis; mRNA Expression; macrophage; microbial; microbial community; monocyte; mortality; mouse model; neonatal mice; neonatal period; next generation sequencing; novel; nuclear factor-erythroid 2; pathogenic bacteria; preservation; prevent; protective effect; pup; receptor expression; scavenger receptor; single cell analysis; single-cell RNA sequencing; therapeutic development; therapeutically effective; tool

PROJECT SUMMARY/ABSTRACT Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in preterm infants in the neonatal intensive care unit (NICU). The discovery of effective therapeutic and preventative strategies against NEC remains an ongoing priority. Although the multiple components of the innate and adaptive immune system have a described role in the pathogenesis of NEC, the overall immune cell signature during NEC compared to intestinal homeostasis has not been described. Preliminary data has shown the important anti-inflammatory role of the aryl hydrocarbon receptor and its dietary ligand, indole-3-carbinol, in attenuating inflammation during NEC and preserving intestinal architecture. The preliminary data further shows that mice lacking AhR in CD11c+ cells (AhR∆CD11c) have an increased expression of pro-inflammatory IL-1β during NEC, whereas mice lacking AhR in the intestinal epithelial cells (IEC) (AhR∆IEC) experience no difference in the severity of NEC. The anti- inflammatory functions of some dietary AhR ligands have been described in adult experimental colitis, but their role in NEC is unknown. Therefore, this proposal tests the central hypothesis that the inflammation in the small intestine of infants with NEC contains a distinct immune cell infiltrate and that dietary AhR ligands activate signaling pathways during NEC to attenuate the inflammatory response. This proposal will use next generation sequencing tools to evaluate the immune cell infiltrate of the small intestine during our experimental murine model of NEC and in surgically resected human small intestine NEC tissue. Further, the effects of a dietary AhR ligand on the pro-inflammatory response and epithelial barrier dysfunction during NEC will be investigated using our experimental murine NEC in wild-type mice, mice with AhR cell-specific knockouts, and human preterm enteroids. This research has significant translational relevance and addresses a critical knowledge gap in the understanding of the immune-related mechanisms in NEC pathogenesis. The outcomes of this work will define how a dietary ligand supplement to infants with immature immunity and immure gut barrier function may serve as a novel immunotherapeutic and nutritional strategy to protect the intestine against this deadly disease.

项目总结/摘要 坏死性小肠结肠炎（NEC）仍然是早产儿发病率和死亡率的重要原因， 新生儿重症监护室（NICU）。发现有效的治疗和预防策略， NEC仍然是一个持续的优先事项。虽然先天性和适应性免疫系统的多种成分 在NEC的发病机制中具有所述的作用，NEC期间的总体免疫细胞特征与 肠内稳态尚未被描述。初步数据显示， 芳香烃受体及其饮食配体吲哚-3-甲醇在减轻NEC期间的炎症中的作用 和保护肠道结构。初步数据进一步表明，在CD 11 c+细胞中缺乏AhR的小鼠 (AhR在NEC过程中，AhR缺乏的小鼠（CD 11 c）的促炎性IL-1β表达增加，而在NEC过程中， 肠上皮细胞（IEC）（AhR/IEC）在NEC的严重程度上没有差异。反- 一些饮食AhR配体的炎症功能已经在成人实验性结肠炎中被描述，但是它们的 在NEC中的作用未知。因此，这项建议测试了中心假设，即炎症在小 患有NEC婴儿的肠道含有明显的免疫细胞浸润，且饮食AhR配体被激活 在NEC过程中的信号通路，以减弱炎症反应。该提案将使用下一代 测序工具，以评估免疫细胞浸润的小肠在我们的实验鼠 NEC模型和手术切除的人小肠NEC组织。此外，饮食AhR的影响 在NEC过程中，将使用以下方法研究配体对促炎反应和上皮屏障功能障碍的影响 我们在野生型小鼠、AhR细胞特异性敲除小鼠和人类早产儿中进行的实验性小鼠NEC 肠状体。这项研究具有重要的翻译相关性，并解决了关键的知识差距， 了解NEC发病机制中的免疫相关机制。这项工作的成果将确定 膳食配体补充剂对免疫力不成熟和肠道屏障功能不完善婴儿的作用 作为一种新的免疫和营养策略，以保护肠道免受这种致命疾病的侵害。