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
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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

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Figure 5

ARRDC3 promotes neutrophil accumulation in gastric mucosa in vivo and migration in vitro during H. pylori infection via CXCL2.

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ARRDC3 promotes neutrophil accumulation in gastric mucosa in vivo and mi...
(A) The expression of chemokine family members in gastric mucosa of WT H. pylori–infected WT and Arrdc3–/– mice on day 28 p.i. was analyzed by real-time PCR (n = 5). (B) CXCL2 expression in gastric mucosa of WT H. pylori–infected WT and Arrdc3–/– mice (n = 6) or in gastric mucosa of WT H. pylori–infected BM chimera mice (n = 5) on day 28 p.i. was compared. (C) ARRDC3 siRNA, nonspecific control siRNA (NC), or lipo3000 only (mock) pretreated AGS cells or AGS cells without treatment (medium) and primary gastric epithelial cells (GECs) from uninfected WT and Arrdc3–/– mice were infected with WT H. pylori (MOI = 100) for 24 hours. CXCL2 production was measured in cell culture supernatants by ELISA (n = 3). (D) CXCR2 expression on human CD45+CD11b+CD14–CD66b+ neutrophils in blood of H. pylori–infected patients or on mouse CD45+CD11b+Ly6C–Ly6G+ neutrophils in blood of WT H. pylori–infected mice on day 28 p.i. (E) CD45+CD11b+Ly6C–Ly6G+ neutrophil levels in gastric mucosa of WT H. pylori–infected mice injected with CXCL2 or PBS control, or Abs against CXCL2 and/or Abs against CXCR2 or corresponding isotype control Abs on day 28 p.i. were compared (n = 5). (F and G) Human CD45+CD11b+CD14–CD66b+ neutrophil migration (F) and mouse CD45+CD11b+Ly6C–Ly6G+ neutrophil migration (G) was assessed by transwell assays as described in Methods and statistically analyzed (n = 5). Data are representative of 2 independent experiments. Data are mean ± SEM and analyzed by Student t test, Mann-Whitney U test, and 1-way ANOVA. *P < 0.05, **P < 0.01 for groups connected by horizontal lines. sup, supernatant.