机构：[1]National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China.[2]Department of Clinical Laboratory, the General Hospital of Western Theater Command, Chengdu, Sichuan, China.[3]Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, and.[4]Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China.[5]La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Victoria, Australia.[6]Department of Hepatobiliary Surgery, XinQiao Hospital, Third Military Medical University, Chongqing, China.
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.
基金：
This work was supported by the National Key Research and Development Program of China
(2016YFC1302200) and grant of National Natural Science Foundation of China (81870394 and 81872016).
第一作者机构：[1]National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China.[2]Department of Clinical Laboratory, the General Hospital of Western Theater Command, Chengdu, Sichuan, China.
共同第一作者：
通讯作者：
通讯机构：[1]National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China.[6]Department of Hepatobiliary Surgery, XinQiao Hospital, Third Military Medical University, Chongqing, China.[*1]National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, No.30 Gaotanyan Street, Chongqing 400038, China.[*2]Department of Hepatobiliary Surgery, XinQiao Hospital, Third Military Medical University, Chongqing 400037, China.
推荐引用方式(GB/T 7714)：
Liu Yu-Gang,Teng Yong-Sheng,Shan Zhi-Guo,et al.Arrestin domain containing 3 promotes Helicobacter pylori-associated gastritis by regulating protease-activated receptor 1.[J].JCI insight.2020,5(15):doi:10.1172/jci.insight.135849.
APA：
Liu Yu-Gang,Teng Yong-Sheng,Shan Zhi-Guo,Cheng Ping,Hao Chuan-Jie...&Zhuang Yuan.(2020).Arrestin domain containing 3 promotes Helicobacter pylori-associated gastritis by regulating protease-activated receptor 1..JCI insight,5,(15)
MLA：
Liu Yu-Gang,et al."Arrestin domain containing 3 promotes Helicobacter pylori-associated gastritis by regulating protease-activated receptor 1.".JCI insight 5..15(2020)
医学