Type 2 inflammation is associated with epithelial cell responses, including goblet cell hyperplasia, that promote worm expulsion during intestinal helminth infection. How these epithelial responses are regulated remains incompletely understood. Here, we show that mice deficient in the prostaglandin D₂ (PGD₂) receptor CRTH2 and mice with CRTH2 deficiency only in nonhematopoietic cells exhibited enhanced worm clearance and intestinal goblet cell hyperplasia following infection with the helminth Nippostrongylus brasiliensis. Small intestinal stem, goblet, and tuft cells expressed CRTH2. CRTH2-deficient small intestinal organoids showed enhanced budding and terminal differentiation to the goblet cell lineage. During helminth infection or in organoids, PGD₂ and CRTH2 down-regulated intestinal epithelial Il13ra1 expression and reversed Type 2 cytokine–mediated suppression of epithelial cell proliferation and promotion of goblet cell accumulation. These data show that the PGD₂–CRTH2 pathway negatively regulates the Type 2 cytokine–driven epithelial program, revealing a mechanism that can temper the highly inflammatory effects of the anti-helminth response.

中文翻译：

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PGD​​ 2 和 CRTH2 抵消蠕虫感染期间 2 型细胞因子引起的肠上皮反应


2 型炎症与上皮细胞反应有关，包括杯状细胞增生，在肠道蠕虫感染期间促进蠕虫排出。这些上皮反应是如何调节的仍不完全清楚。在这里，我们发现前列腺素 D ₂ (PGD ₂ ) 受体 CRTH2 缺陷的小鼠和仅非造血细胞中 CRTH2 缺陷的小鼠在感染巴西圆线虫后表现出蠕虫清除能力增强和肠杯状细胞增生。小肠干细胞、杯状细胞和簇状细胞表达 CRTH2。 CRTH2 缺陷的小肠类器官表现出向杯状细胞谱系的出芽和终末分化增强。在蠕虫感染期间或在类器官中，PGD ₂和 CRTH2 下调肠上皮Il13ra1表达，并逆转 2 型细胞因子介导的上皮细胞增殖抑制和杯状细胞积累促进。这些数据表明，PGD ₂ –CRTH2 途径对 2 型细胞因子驱动的上皮细胞程序产生负调节，揭示了一种可以缓和抗蠕虫反应的高度炎症效应的机制。