Yuan Hanmei, Li Yuetong, Wu Hui, Zhang Jin, Xia Tingting, Li Bin, Wu Chao
Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
Department of Endocrinology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
Helicobacter. 2025 May-Jun;30(3):e70042. doi: 10.1111/hel.70042.
Helicobacter pylori (H. pylori) infection is one of the most important risk factors for chronic gastritis, gastric ulcers, and gastric cancer. Mast cells act as a crucial regulator in bacterial infection. The mechanisms underlying mast cell activation and their role in H. pylori infection remain poorly understood.
In gastric mucosal tissue, the number of mast cells, G-protein-coupled receptor 171 (GPR171) and CCL2 expression were detected by immunohistochemistry (IHC) or immunofluorescence between H. pylori-negative and H. pylori-positive patients. Mast cells were co-cultured with H. pylori, and transcriptome sequencing, RT-qPCR, and Western blotting (WB) were performed to identify receptors involved in mast cell activation. WB, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays were conducted to investigate the molecular mechanism by which HIF-1α regulates GPR171 expression. Lentiviral knockdown, ELISA, WB, and IHC were used to evaluate the role of GPR171 during H. pylori infection. An in vivo mouse model of H. pylori infection was employed to assess the effects of GPR171 blockade on CCL2 expression and gastric mucosal inflammation.
In the study, we found that mast cell numbers were greatly increased and correlated with the severity of inflammation in H. pylori-infected patients. We found a new receptor, GPR171, was upregulated and involved in mast cell activation upon H. pylori infection. Furthermore, H. pylori infection induced the expression of GPR171 by promoting the activation of hypoxia-inducible factor 1 alpha (HIF-1α), which directly bound to hypoxia response elements in the GPR171 promoter and regulated its transcriptional activity. Blockade or loss of GPR171 in mast cells partially inhibited CCL2 secretion via the ERK1/2 signaling pathway. In the human gastric mucosa, CCL2 derived from mast cells was associated with gastric inflammation during H. pylori infection. In vivo murine studies indicated that H. pylori infection significantly upregulated CCL2 expression, while GPR171 inhibition partially reduced CCL2 levels and alleviated gastric mucosal inflammation.
We provide a novel mechanism that H. pylori activates mast cells to promote gastric inflammation.
幽门螺杆菌（H. pylori）感染是慢性胃炎、胃溃疡和胃癌最重要的危险因素之一。肥大细胞在细菌感染中起关键调节作用。肥大细胞激活的潜在机制及其在幽门螺杆菌感染中的作用仍知之甚少。
在胃黏膜组织中，通过免疫组织化学（IHC）或免疫荧光检测幽门螺杆菌阴性和阳性患者之间肥大细胞的数量、G蛋白偶联受体171（GPR171）和CCL2的表达。将肥大细胞与幽门螺杆菌共培养，并进行转录组测序、RT-qPCR和蛋白质印迹法（WB）以鉴定参与肥大细胞激活的受体。进行WB、染色质免疫沉淀（ChIP）和双荧光素酶报告基因测定以研究HIF-1α调节GPR171表达的分子机制。使用慢病毒敲低、ELISA、WB和IHC来评估GPR171在幽门螺杆菌感染期间的作用。采用幽门螺杆菌感染的体内小鼠模型来评估GPR171阻断对CCL2表达和胃黏膜炎症的影响。
在本研究中，我们发现幽门螺杆菌感染患者的肥大细胞数量大幅增加，且与炎症严重程度相关。我们发现一种新的受体GPR171在幽门螺杆菌感染后上调并参与肥大细胞激活。此外，幽门螺杆菌感染通过促进缺氧诱导因子1α（HIF-1α）的激活诱导GPR171的表达，HIF-1α直接与GPR171启动子中的缺氧反应元件结合并调节其转录活性。肥大细胞中GPR171的阻断或缺失通过ERK1/2信号通路部分抑制CCL2分泌。在人胃黏膜中，肥大细胞衍生的CCL2与幽门螺杆菌感染期间的胃炎症相关。体内小鼠研究表明，幽门螺杆菌感染显著上调CCL2表达，而GPR171抑制可部分降低CCL2水平并减轻胃黏膜炎症。
我们提供了一种新机制，即幽门螺杆菌激活肥大细胞以促进胃炎症。
