Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Immunity. 2024 Jun 11;57(6):1243-1259.e8. doi: 10.1016/j.immuni.2024.03.023. Epub 2024 May 13.
Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.
肠上皮细胞分泌氯化物以调节黏膜屏障的水分释放，支持水盐平衡和“流泪”反应，这对于 2 型免疫防御寄生虫（蠕虫）至关重要。小肠中的上皮簇细胞感知蠕虫并释放细胞因子和脂质以激活 2 型免疫细胞，但它们是否调节上皮细胞分泌尚不清楚。在这里，我们发现簇细胞的激活会迅速诱导小肠中的上皮氯化物分泌。这种反应需要簇细胞的感觉功能和簇细胞衍生的乙酰胆碱（ACh），它直接作用于邻近的上皮细胞以刺激氯化物分泌，而不依赖于神经元。簇细胞诱导的最大氯化物分泌与蠕虫的免疫限制相吻合，并且在缺乏簇细胞衍生的 ACh 的小鼠中清除被延迟，尽管 2 型炎症正常。因此，我们发现了一个上皮细胞固有反应单元，它使用 ACh 将簇细胞的感应与邻近上皮细胞的分泌防御联系起来。
