1. Inflammation-Associated Senescence Promotes Helicobacter pylori–Induced Atrophic GastritisSummary
- Author
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Yulong He, Jianbo Xu, Peng Shi, Xinde Ou, Wen Zhou, Shirong Cai, Jin Li, Yujie Yuan, Jianjun Peng, Taiqiang Su, Liangliang Lin, and Qinbo Cai
- Subjects
0301 basic medicine ,Chemokine ,Atrophic gastritis ,RELA, RELA proto-oncogene, nuclear factor-κB subunit ,TP53, tumor protein p53 ,BrdU, bromodeoxyuridine ,Chemokine receptor ,0302 clinical medicine ,CG, chronic gastritis ,GSEA, gene set enrichment analysis ,CXCL, C-X-C motif chemokine ligand ,GEO, Gene Expression Omnibus ,CXC chemokine receptors ,Helicobacter ,MOI, multiplicity of infection ,Original Research ,biology ,H pylori ,Gastroenterology ,IM, intestinal metaplasia ,MNU, N-methyl-N-nitrosourea ,mRNA, messenger RNA ,PMSS1, pre-mouse Sydney strain 1 ,ChIP, chromatin immunoprecipitation ,medicine.anatomical_structure ,CXCR2, C-X-C motif chemokine receptor 2 ,qPCR, quantitative polymerase chain reaction ,030211 gastroenterology & hepatology ,CagA, cytotoxin-associated gene A ,CDKN, cyclin-dependent kinase inhibitor ,Gastritis, Atrophic ,Senescence ,PBS, phosphate-buffered saline ,IHC, immunohistochemical ,NF-κB, nuclear factor-κB ,SASP, senescence-associated secretory phenotype ,C-X-C Motif Chemokine Receptor 2 ,NFKB1, nuclear factor-κB subunit 1 ,Helicobacter Infections ,Senescent Cell ,03 medical and health sciences ,Gastric mucosa ,medicine ,Humans ,lcsh:RC799-869 ,Helicobacter pylori ,Hepatology ,Mucosa Atrophy ,AG, atrophic gastritis ,biology.organism_classification ,medicine.disease ,IL, interleukin ,030104 developmental biology ,biology.protein ,Cancer research ,lcsh:Diseases of the digestive system. Gastroenterology ,DP, dysplasia ,Atrophy - Abstract
Background & Aims The association between cellular senescence and Helicobacter pylori–induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori–induced atrophic gastritis and the underlying mechanism. Methods C57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro. Results Gastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori–infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression. Conclusions Our study showed a new mechanism of H pylori–induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori–induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556., Graphical abstract
- Published
- 2021