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

<p dir="ltr">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 <i>Helicobacter pylori</i>–associated gastritis. Increased ARRDC3 was detected in gastric mucosa of patients and mice infected with <i>H</i>. <i>pylori</i>. ARRDC3 in gastric epithelial cells (GECs) was induced by <i>H</i>. <i>pylori</i>, regulated by ERK and PI3K-AKT pathways in a <i>cagA</i>-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 <i>Arrdc3</i>^{<em>–/–</em>} mice but increased in protease-activated receptor 1^–/– (<i>Par1</i>^–/–) 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 <i>H</i>. <i>pylori</i>–associated gastritis. This study identifies a regulatory network involving <i>H</i>. <i>pylori</i>, 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 <i>H</i>. <i>pylori</i>–associated gastritis.</p>