Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis.
Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis.
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DOI：
10.7554/elife.67292
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发表时间：
2021-10-22
期刊：
影响因子：
7.7
通讯作者：
Newberry RD
中科院分区：
文献类型：
--
作者：
Gustafsson JK;Davis JE;Rappai T;McDonald KG;Kulkarni DH;Knoop KA;Hogan SP;Fitzpatrick JA;Lencer WI;Newberry RD
肠杯状细胞通过粘液分泌维持保护性上皮屏障，并且还通过形成杯状细胞相关抗原通道（GAP）来取样内腔物质用于免疫加工。GAP的细胞生物学以及杯状细胞如何平衡和调节这些不同的过程仍然是未知的。使用高分辨率光学和电子显微镜，我们发现，在小鼠中，GAP是由乙酰胆碱（ACh）依赖性内吞事件显着的交付流体相货物逆行到trans-golgi网络和跨细胞的转胞吞作用-除了预期的运输流体相货物的内体多囊泡体和溶酶体。虽然乙酰胆碱也诱导杯状细胞分泌粘蛋白，乙酰胆碱诱导的GAP形成和粘蛋白分泌功能独立，并介导不同的受体和信号通路，使杯状细胞差异调节这些过程，以适应动态变化的需求粘膜环境的屏障维护和采样的内腔物质。肠道中的细胞需要受到保护，免受居住在这种环境中的许多有害微生物的侵害。然而，免疫系统也需要“密切关注”肠道内容物，以保持对无害物质的耐受性，例如饮食中的物质。作为肠道内壁一部分的“杯状细胞”同时具有这两种功能：它们创造了一个粘液屏障，阻止细菌入侵身体，但它们也可以将分子从肠道传递到组织深处的免疫细胞，以促进耐受性。这是通过“GAP”机制实现的。一种叫做乙酰胆碱的化学信使可以触发粘液释放和杯状细胞中差距过程。Gustafsson等人研究了细胞如何在响应相同信号时承担这两种看似相反的角色。一种荧光分子被引入小鼠的肠道，并在它通过杯状细胞时进行监测。这揭示了差距过程是如何发生的：细胞能够从肠道捕获分子，将它们包裹在内部囊状囊泡中，然后将它们运输到整个细胞中。为了探索乙酰胆碱的作用，Gustafsson等人阻断了杯状细胞表面检测信使的受体。发现不同的受体和因此不同的分子事件级联控制粘液分泌和GAP形成;这解释了这两个过程如何可以平行且彼此独立地进行。了解细胞如何将分子传递到免疫系统与其他与环境接触的组织有关，如眼睛，气道或生殖器和尿道内部。了解并最终利用这种机制可以帮助设计新的方法来将药物输送到免疫系统并改变免疫结果。
Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis – in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and lysosomes. While ACh also induced goblet cells to secrete mucins, ACh-induced GAP formation and mucin secretion were functionally independent and mediated by different receptors and signaling pathways, enabling goblet cells to differentially regulate these processes to accommodate the dynamically changing demands of the mucosal environment for barrier maintenance and sampling of lumenal substances. Cells in the gut need to be protected against the many harmful microbes which inhabit this environment. Yet the immune system also needs to ‘keep an eye’ on intestinal contents to maintain tolerance to innocuous substances, such as those from the diet. The ‘goblet cells’ that are part of the gut lining do both: they create a mucus barrier that stops germs from invading the body, but they also can pass on molecules from the intestine to immune cells deep in the tissue to promote tolerance. This is achieved through a ‘GAP’ mechanism. A chemical messenger called acetylcholine can trigger both mucus release and the GAP process in goblet cells. Gustafsson et al. investigated how the cells could take on these two seemingly opposing roles in response to the same signal. A fluorescent molecule was introduced into the intestines of mice, and monitored as it pass through the goblet cells. This revealed how the GAP process took place: the cells were able to capture molecules from the intestines, wrap them in internal sack-like vesicles and then transport them across the entire cell. To explore the role of acetylcholine, Gustafsson et al. blocked the receptors that detect the messenger at the surface of goblet cells. Different receptors and therefore different cascades of molecular events were found to control mucus secretion and GAP formation; this explains how the two processes can be performed in parallel and independently from each other. Understanding how cells relay molecules to the immune system is relevant to other tissues in contact with the environment, such as the eyes, the airways, or the inside of the genital and urinary tracts. Understanding, and then ultimately harnessing this mechanism could help design of new ways to deliver drugs to the immune system and alter immune outcomes.