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

项目摘要/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。 新生儿重症监护病房(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。尽管先天免疫系统和获得性免疫系统的多种成分 在NEC的发病机制中有描述的作用，与NEC相比，NEC期间的总体免疫细胞特征 肠道内环境平衡尚未被描述。初步数据显示其具有重要的抗炎作用。 芳香烃受体及其饮食配体吲哚-3-甲醇在NEC中的抗炎作用 和保护肠道结构。初步数据进一步表明，CD11c+细胞中缺乏AhR的小鼠 (AHR∆CD11c)在NEC过程中促炎IL-1β表达增加，而缺乏AhR的小鼠 肠上皮细胞(AhR、∆、肠上皮细胞)的严重程度无差异。反- 一些饮食中的AhR配体在成人实验性结肠炎中的炎症功能已被描述，但他们的 NEC中的角色尚不清楚。因此，这一提议检验了中心假说，即小鼠的炎症 NEC患儿肠道内有明显的免疫细胞浸润和膳食AhR配体的激活 NEC过程中减轻炎症反应的信号通路。这项提议将使用下一代 用测序工具评估实验小鼠小肠免疫细胞的渗入 NEC模型及手术切除的人小肠NEC组织。此外，膳食AHR的影响 配体在NEC期间的促炎反应和上皮屏障功能障碍方面的研究将使用 我们在野生型小鼠、AhR细胞特异性敲除小鼠和人类早产小鼠中的实验小鼠NEC 肠状突。这项研究具有重要的翻译相关性，并解决了翻译中的关键知识差距 了解NEC发病的免疫相关机制。这项工作的成果将确定 饮食配基补充剂对免疫不成熟和肠道屏障功能障碍的婴儿有何作用 作为一种新的免疫治疗和营养策略，以保护肠道免受这种致命疾病的侵袭。

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.