HIF-1α-Induced GPR171 Expression Mediates CCL2 Secretion by Mast Cells to Promote Gastric Inflammation During Helicobacter pylori Infection

IF 4.3 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Helicobacter Pub Date : 2025-05-04 DOI:10.1111/hel.70042

Hanmei Yuan, Yuetong Li, Hui Wu, Jin Zhang, Tingting Xia, Bin Li, Chao Wu

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Abstract

Background

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.

Materials and Methods

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.

Results

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.

Conclusions

We provide a novel mechanism that H. pylori activates mast cells to promote gastric inflammation.

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hif -1α-诱导GPR171表达介导肥大细胞分泌CCL2促进幽门螺杆菌感染胃炎症

背景幽门螺杆菌感染是慢性胃炎、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着至关重要的调节作用。肥大细胞激活的机制及其在幽门螺杆菌感染中的作用仍然知之甚少。材料与方法采用免疫组化（IHC）或免疫荧光法检测胃粘膜肥大细胞数量、g蛋白偶联受体171 （GPR171）和CCL2的表达。肥大细胞与幽门螺杆菌共培养，通过转录组测序、RT-qPCR和Western blotting （WB）鉴定参与肥大细胞活化的受体。采用WB、染色质免疫沉淀（ChIP）和双荧光素酶报告基因法研究HIF-1α调控GPR171表达的分子机制。采用慢病毒敲除、ELISA、WB和免疫组化方法评价GPR171在幽门螺杆菌感染中的作用。采用幽门螺杆菌感染小鼠体内模型，研究阻断GPR171对CCL2表达及胃黏膜炎症的影响。结果本研究发现，幽门螺杆菌感染患者肥大细胞数量显著增加，且肥大细胞数量与炎症严重程度相关。我们发现一种新的受体GPR171在幽门螺杆菌感染时被上调并参与肥大细胞的激活。此外，幽门螺杆菌感染通过促进缺氧诱导因子1α (HIF-1α)的激活来诱导GPR171的表达，HIF-1α直接结合GPR171启动子中的缺氧反应元件并调节其转录活性。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的分泌。在人胃粘膜中，源自肥大细胞的CCL2与幽门螺杆菌感染期间的胃炎症有关。小鼠体内研究表明，幽门螺杆菌感染可显著上调CCL2表达，而抑制GPR171可部分降低CCL2水平，减轻胃黏膜炎症。结论提供了一种新的幽门螺旋杆菌激活肥大细胞促进胃炎症的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Helicobacter 医学-微生物学

CiteScore

8.40

自引率

9.10%

发文量

审稿时长

2 months

期刊介绍： Helicobacter is edited by Professor David Y Graham. The editorial and peer review process is an independent process. Whenever there is a conflict of interest, the editor and editorial board will declare their interests and affiliations. Helicobacter recognises the critical role that has been established for Helicobacter pylori in peptic ulcer, gastric adenocarcinoma, and primary gastric lymphoma. As new helicobacter species are now regularly being discovered, Helicobacter covers the entire range of helicobacter research, increasing communication among the fields of gastroenterology; microbiology; vaccine development; laboratory animal science.