Helicobacter pylori is a pathogen that colonizes the stomach and causes chronic gastritis. Helicobacter pylori can colonize deep inside gastric glands, triggering increased R-spondin 3 (Rspo3) signaling. This causes an expansion of the “gland base module,” which consists of self-renewing stem cells and antimicrobial secretory cells and results in gland hyperplasia. The contribution of Rspo3 receptors Lgr4 and Lgr5 is not well explored. Here, we identified that Lgr4 regulates Lgr5 expression and is required for H. pylori-induced hyperplasia and inflammation, while Lgr5 alone is not. Using conditional knockout mice, we reveal that R-spondin signaling via Lgr4 drives proliferation of stem cells and also induces NF-κB activity in the proliferative stem cells. Upon exposure to H. pylori, the Lgr4-driven NF-κB activation is responsible for the expansion of the gland base module and simultaneously enables chemokine expression in stem cells, resulting in gland hyperplasia and neutrophil recruitment. This demonstrates a connection between R-spondin-Lgr and NF-κB signaling that links epithelial stem cell behavior and inflammatory responses to gland-invading H. pylori.

中文翻译：

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胃干细胞通过 Rspo3-Lgr4 轴促进对幽门螺杆菌的炎症和腺体重塑

幽门螺杆菌是一种定植于胃并引起慢性胃炎的病原体。幽门螺杆菌可以在胃腺深处定殖，触发增加的 R-spondin 3 (Rspo3) 信号。这导致“腺体基础模块”的扩展，该模块由自我更新的干细胞和抗菌分泌细胞组成，并导致腺体增生。Rspo3 受体 Lgr4 和 Lgr5 的贡献没有得到很好的探索。在这里，我们发现 Lgr4 调节 Lgr5 表达并且是幽门螺杆菌所必需的-诱导的增生和炎症，而单独的 Lgr5 则不是。使用条件性敲除小鼠，我们揭示了通过 Lgr4 的 R-spondin 信号传导驱动干细胞的增殖并诱导增殖干细胞中的 NF-κB 活性。暴露于幽门螺杆菌后，Lgr4 驱动的 NF-κB 激活负责腺体基础模块的扩展，同时使干细胞中的趋化因子表达成为可能，导致腺体增生和中性粒细胞募集。这证明了 R-spondin-Lgr 和 NF-κB 信号之间的联系，该信号将上皮干细胞行为和炎症反应与腺体入侵的幽门螺杆菌联系起来。