Arrestin domain containing 3 promotes Helicobacter pylori–associated gastritis by regulating protease-activated receptor 1
Yu-gang Liu, Yong-sheng Teng, Zhi-guo Shan, Ping Cheng, Chuan-jie Hao, Yi-pin Lv, Fang-yuan Mao, Shi-ming Yang, Weisan Chen, Yong-liang Zhao, Nan You, Quan-ming Zou, Yuan Zhuang
Yu-gang Liu, Yong-sheng Teng, Zhi-guo Shan, Ping Cheng, Chuan-jie Hao, Yi-pin Lv, Fang-yuan Mao, Shi-ming Yang, Weisan Chen, Yong-liang Zhao, Nan You, Quan-ming Zou, Yuan Zhuang
View: Text | PDF
Research Article Gastroenterology Infectious disease

Arrestin domain containing 3 promotes Helicobacter pylori–associated gastritis by regulating protease-activated receptor 1

Abstract

Arrestin domain containing 3 (ARRDC3) represents a newly discovered α-arrestin involved in obesity, inflammation, and cancer. Here, we demonstrate a proinflammation role of ARRDC3 in Helicobacter pylori–associated gastritis. Increased ARRDC3 was detected in gastric mucosa of patients and mice infected with H. pylori. ARRDC3 in gastric epithelial cells (GECs) was induced by H. pylori, regulated by ERK and PI3K-AKT pathways in a cagA-dependent manner. Human gastric ARRDC3 correlated with the severity of gastritis, and mouse ARRDC3 from non-BM–derived cells promoted gastric inflammation. This inflammation was characterized by the CXCR2-dependent influx of CD45+CD11b+Ly6C–Ly6G+ neutrophils, whose migration was induced via the ARRDC3-dependent production of CXCL2 by GECs. Importantly, gastric inflammation was attenuated in Arrdc3–/– mice but increased in protease-activated receptor 1–/– (Par1–/–) mice. Mechanistically, ARRDC3 in GECs directly interacted with PAR1 and negatively regulated PAR1 via ARRDC3-mediated lysosomal degradation, which abrogated the suppression of CXCL2 production and following neutrophil chemotaxis by PAR1, thereby contributing to the development of H. pylori–associated gastritis. This study identifies a regulatory network involving H. pylori, GECs, ARRDC3, PAR1, and neutrophils, which collectively exert a proinflammatory effect within the gastric microenvironment. Efforts to inhibit this ARRDC3-dependent pathway may provide valuable strategies in treating of H. pylori–associated gastritis.

Authors

Yu-gang Liu, Yong-sheng Teng, Zhi-guo Shan, Ping Cheng, Chuan-jie Hao, Yi-pin Lv, Fang-yuan Mao, Shi-ming Yang, Weisan Chen, Yong-liang Zhao, Nan You, Quan-ming Zou, Yuan Zhuang

×

Figure 2

H. pylori stimulates gastric epithelial cells to express ARRDC3.

Options: View larger image (or click on image) Download as PowerPoint
H. pylori stimulates gastric epithelial cells to express ARRDC3. (A and...
(A and B) Representative immunofluorescence staining images showing ARRDC3-expressing (red) CD326+ (green) gastric epithelial cells (GECs), ARRDC3-expressing (red) H+/K+ ATPase+ (green) parietal cells, and ARRDC3-expressing (red) pepsinogen II+ chief cells (green) in gastric mucosa of H. pylori–infected patients (A) or H. pylori–infected mice (B). Scale bars: 100 μm. (C) The expression of arrestin family members in WT H. pylori–infected and uninfected AGS cells (MOI = 100, 6 hours) was analyzed by real-time PCR (n = 4). (D and G) ARRDC3 expression and ARRDC3 protein in WT H. pylori–infected and uninfected AGS cells at different time points (MOI = 100) or with different MOI (24 hours) were analyzed by real-time PCR and Western blot (n = 3). (E–G) ARRDC3 expression and ARRDC3 protein in WT H. pylori–infected, ΔcagA-infected, and uninfected AGS cells (E and G) and human primary gastric epithelial cells (F and G) (MOI = 100, 24 hours) were analyzed by real-time PCR and Western blot (n = 3). Data are representative of 2 independent experiments. Data are mean ± SEM and analyzed by 1-way ANOVA. Western blot results are run in parallel and contemporaneously. *P < 0.05, **P < 0.01 for groups connected by horizontal lines.