Development and Function of Biliary Tuft Cells

项目总结 胆道系统储存、调节和提供胆汁的排泄，从而有必要暴露于潜在的 破坏性的，高度酸性的流明内容物。维持坚固的上皮屏障，有限的免疫反应 对正常胆汁的扰动，以及腔内致病性和非致病性改变的鉴别 胆汁内含物对体内平衡胆汁功能至关重要。屏障功能障碍或异常的免疫调节可导致 炎症是胆道疾病疾病进展的一个关键组成部分。尽管 胆汁静止在肝胆系统功能中的关键作用，我们对体内平衡的理解 胆汁树中的免疫调节是有限的。一条线索可能是胆管中大量的簇状细胞。 上皮组织。簇状细胞，具有化学感觉机制的分泌上皮细胞，形成免疫细胞的“回路”。 在簇状细胞所在的小肠中，IL-25促进天然淋巴样细胞产生IL-13。是否 簇状细胞在其他组织中也有类似的免疫或组织调节作用，但现在才开始探索。我们有 发现胆管簇状细胞表达核心簇状细胞基因程序，这是一种组织特有的基因特征，并且 对胆汁酸生产中的扰动敏感。来自簇状细胞的胆管和肝外导管的分析 缺陷小鼠表明，在没有簇状细胞的情况下，免疫细胞在这个组织中异常聚集。已知的 绒毛细胞在小肠中的作用提示胆管绒毛细胞可能起到整合胆管上皮的作用 与免疫系统有关；与小肠相比，我们的数据表明胆管绒毛细胞可以抑制 炎症反应。总而言之，这表明胆管绒毛细胞在胆汁酸中可能发挥着不可估量的作用。 感知或适应对胆汁酸丰度的反应，并可能调节胆汁免疫反应。 这一建议将检验胆管绒毛细胞丰度受胆汁含量控制的假设，以及 这种簇状细胞在体内稳态时抑制胆道免疫反应。我们将利用敏感的IL-25 以活体工具为基础来描述丛生细胞的丰度、位置和发育调节 胆汁树。我们将试图了解胆汁酸操作影响胆管小束的机制。 使用体外和体内方法的细胞丰度。我们将评估丛生细胞如何调节免疫。 胆道树的“音调”，以及在感染过程中可能产生的后果。秘密的和 丛状细胞的化学感觉功能使这些细胞吸引胆汁含量与组织整合的人 或免疫细胞反应，而胆管绒毛细胞独特的基因表达谱表明具有治疗作用 延展性。除了可能定义胆管绒毛细胞的新的组织特异性作用外，我们的工作还将 增加了关于胆道免疫反应的现有知识，以及对 胆管上皮细胞、间质细胞和免疫细胞。未来的研究将在更复杂的情况下研究簇状细胞的功能 肝胆管炎症和疾病模型的建立及簇状细胞丰度与人体相关性的探讨 胆道疾病状态，具有在胆道病理学中推进新治疗靶点的巨大潜力。

PROJECT SUMMARY The biliary system stores, modifies, and provides regulated excretion of bile, necessitating exposure to potentially damaging, highly acidic luminal contents. Maintenance of a robust epithelial barrier, limited immune responses to normal bile perturbations, and discrimination between pathogenic and non-pathogenic changes in luminal contents are critical to homeostatic biliary function. Barrier failure or aberrant immune regulation can lead to inflammation, a key component of disease progression in biliary diseases known as cholangiopathies. Despite the critical role biliary quiescence plays in function of the hepatobiliary system, our understanding of homeostatic immune regulation in the biliary tree is limited. One clue may be the striking abundance of tuft cells in the biliary epithelium. Tuft cells, secretory epithelial cells with chemosensory machinery, nucleate an immune cell “circuit” in the small intestine in which tuft cell IL-25 promotes the production of IL-13 from innate lymphoid cells. Whether similar immune or tissue-modulating roles for tuft cells exist in other tissues is only now being explored. We have found that biliary tuft cells express the core tuft cell gene program, a tissue-specific gene signature, and are sensitive to perturbations in bile acid production. Analysis of gallbladder and extrahepatic ducts from tuft cell deficient mice indicates aberrant immune cell accumulation in this tissue in the absence of tuft cells. The known roles of tuft cells in the small intestine suggests that biliary tuft cells could serve to integrate the biliary epithelium with the immune system; in contrast to the small intestine, our data indicate biliary tuft cells could inhibit inflammatory responses. Together, this suggests that biliary tuft cells could play unappreciated roles in bile acid sensing or the adaptive response to perturbed bile acid abundance, and may regulate biliary immune responses. This proposal will test the hypothesis that biliary tuft cell abundance is controlled by bile content, and that tuft cells repress biliary immune responses at homeostasis. We will take advantage of sensitive, IL-25 based in vivo tools to characterize the abundance, position, and developmental regulation of tuft cells throughout the biliary tree. We will seek to understand the mechanism whereby bile acid manipulation impacts biliary tuft cell abundance using in vitro and in vivo approaches. We will assess how tuft cells might regulate the immune “tone” of the biliary tree, and what consequences this may have during infection. The secretory and chemosensory functions attributed to tuft cells make these cells attractive integrators of bile content with tissue or immune cell responses, while the unique gene expression profile of biliary tuft cells suggests therapeutic malleability. In addition to the potential for defining novel, tissue-specific roles for biliary tuft cells, our work will add to the existing knowledge on biliary immune responses, as well as the understanding of heterogeneity among biliary epithelial, stromal, and immune cells. Future studies will investigate tuft cell function in more complex models of hepatobiliary inflammation and disease and explore the correlation of tuft cell abundance with human biliary disease states, with great potential to advance new therapeutic targets in biliary pathologies.