Novel mechanisms protecting the gut from TNF

项目摘要 肿瘤坏死因子是一种促进宿主防御、细胞存活和组织生长的多效性细胞因子。 然而，在动态平衡条件下，如果失控和过度表达，肿瘤坏死因子是一个主要的驱动力 慢性炎症性疾病。胃肠道中过多的肿瘤坏死因子产生以上皮为靶点，推动 细胞死亡增加，足以引发大量组织炎症和慢性疾病。封锁 肿瘤坏死因子是一种被广泛应用的生物制剂，可用于炎症性肠病的治疗。 (IBD)患者。尽管知道了这一点，但控制药物的有益和有害作用的机制 肠道中的肿瘤坏死因子的定义不明确。这项提议的基本焦点是机械地 定义一种新的途径，保护肠道免受肿瘤坏死因子驱动的损伤和炎症。在……里面 最近发表的新的初步数据，我们已经确定了第3组先天淋巴样细胞(ILC3) 对于保护肠道上皮免受肿瘤坏死因子引起的损伤和炎症是必不可少的。令人惊讶的是，这 它不是通过传统的效应途径发生的，而是与前列腺素的产生和生长有关 各种因素。这些数据引发了一个基本假设，即ILC3对于形成保护性与非保护性 肿瘤坏死因子在肠道中的病理作用，这种平衡在人类IBD中被打破，其中ILC3已知为 变得不受监管。我们将通过提出以下具体问题来机械地检验这一假设： (1)前列腺素感应产生的ILC3如何影响肠道健康和炎症？和(2) ILC3来源的HB-EGF增强肠道免疫的细胞和分子机制是什么 并保护肠道免受肿瘤坏死因子的侵袭？最后，我们将把我们的发现从基本的老鼠模型直接转化为 来自IBD患者的样本。这些实验的结果将为更好地理解 肿瘤坏死因子驱动的肠道损伤和炎症，可能引发新的预防、治疗或 多种慢性炎症性疾病的治疗策略。

PROJECT ABSTRACT Tumor necrosis factor (TNF) is a pleiotropic cytokine that promotes host defense, cell survival and tissue regeneration under homeostatic condition However, if dysregulated and overexpressed, TNF is a major driver of chronic inflammation. Excessive TNF production in the gastrointestinal tract targets the epithelium, drives increased cell death, and is sufficient to elicit substantial tissue inflammation and chronic disease. Blockade of TNF is a widely utilized biologic that provides therapeutic benefit in a subset of inflammatory bowel disease (IBD) patients. Despite this knowledge, the mechanisms that control the beneficial versus detrimental roles of TNF in the intestine are poorly defined. The fundamental focus of this proposal is to mechanistically define a novel pathway that protects the intestine from TNF-driven damage and inflammation. In recently published and new preliminary data, we have determined that group 3 innate lymphoid cells (ILC3s) are essential to protect the intestinal epithelium from TNF-driven damage and inflammation. Surprisingly, this did not occur via traditional effector pathways, and rather involved production of prostaglandins and growth factors. These data provoke a fundamental hypothesis that ILC3s are essential to shape the protective versus pathologic roles of TNF in the intestine, and this balance is disrupted in human IBD where ILC3s are known to become dysregulated. We will mechanistically test this hypothesis by asking the following specific questions: (1) How does ILC3 production of sensing of prostaglandins impact intestinal health and inflammation? And (2) What are the cellular and molecular mechanisms by which ILC3-derived HB-EGF augments intestinal immunity and protects the gut from TNF? Finally, we will directly translate our findings from basic mouse models into samples from IBD patients. Results from these experiments will pave the way for a greater understanding of TNF-driven intestinal damage and inflammation, which could provoke novel preventative, therapeutic or curative strategies for multiple chronic inflammatory diseases.