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

Yu-Gang Liu,Nan You,Weisan Chen,Chuan-Jie Hao,Quan-Ming Zou,Yi-Pin Lv,Yuan Zhuang,Yong-Sheng Teng,Ping Cheng,Shi-Ming Yang,Yong-Liang Zhao,Zhi-Guo Shan,Fang-Yuan Mao

doi:10.1172/jci.insight.135849

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.

Highlights

Helicobacter pylori is a gram-negative bacterium that infects nearly half of the world’s population as gastric pathogen [1]
Arrestin domain containing 3 (ARRDC3) is increased in gastric mucosa of H. pylori–infected patients and mice. o evaluate the potential role of ARRDC3 in H. pylori infection, we first compared the levels of arrestin family members expressed in human primary gastric mucosa of H. pylori–infected and uninfected donors
As cytotoxin associated gene A (cagA) is strongly associated with the development of gastritis [14], we investigated the relationship between cagA and ARRDC3 and found that ARRDC3 expression in cagA-positive patients was significantly higher than that in cagA-negative individuals (Figure 1C)

Summary

Introduction

Helicobacter pylori is a gram-negative bacterium that infects nearly half of the world’s population as gastric pathogen [1]. Persistent H. pylori infection is a key etiological factor in chronic gastritis and peptic ulcer [2]. It was considered the first class of carcinogenic factors for gastric adenocarcinoma by WHO. Arrestins are a family of intracellular proteins that bind to phosphorylated GPCRs and regulate their signal transduction. They are further divided into 3 subfamilies, visual arrestins, β-arrestins, and α-arrestins. Visual arrestins regulate light transduction in photoreceptor cells; like nonvisual arrestins, they are widely distributed and can bind to a wide range of GPCRs to play diverse roles. In different inflammatory diseases, arrestins could play opposite roles.

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