Helicobacter pylori–Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense
| Autor: | Rui Xie, Jingyu Xu, Yong-sheng Teng, Chuan-jie Hao, Shi-Ming Yang, Weisan Chen, Tao Liu, Yi-pin Lv, Yuan Zhuang, Quanming Zou, Fang-yuan Mao, Ping Cheng, Yu-gang Liu |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Chemokine beta-Defensins Th1 T helper type 1 Colony Count Microbial Pancreatitis-Associated Proteins RC799-869 DMSO dimethyl sulfoxide Adaptive Immunity Ab antibody PCR polymerase chain reaction 0302 clinical medicine ERK extracellular signal-regulated kinase Cell Movement M monocyte/macrophage Myeloid Cells MOI multiplicity of infection NF-κB nuclear factor kappa B Original Research Rev-erbα Gastric Epithelial Cells Stomach NF-kappa B Gastroenterology HRP horseradish peroxidase ELISA enzyme-linked immunosorbent assay Middle Aged Diseases of the digestive system. Gastroenterology mRNA messenger RNA ChIP chromatin immunoprecipitation p.i. postinfection medicine.anatomical_structure Host-Pathogen Interactions Host Defense FACS fluorescence-activated cell sorter Female 030211 gastroenterology & hepatology Adult MAP Kinase Signaling System PBS phosphate-buffered saline Biology CFU colony-forming units Models Biological Helicobacter Infections Microbiology Young Adult 03 medical and health sciences Chimera (genetics) GEC gastric epithelial cell NC nonspecific control small interfering RNA FBS fetal bovine serum Bacterial Proteins Antigens CD Immunity Gastric mucosa medicine Humans CagA Aged Antigens Bacterial IFN-γ interferon gamma Helicobacter pylori Hepatology Epithelial Cells Th1 Cells biology.organism_classification WT wild-type Immunity Innate IL interleukin 030104 developmental biology siRNA small interfering RNA Gastric Mucosa Nuclear Receptor Subfamily 1 Group D Member 1 BM bone marrow biology.protein Bone marrow rDNA recombinant DNA CCL21 |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 2, Pp 395-425 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2021.02.013 |
| Popis: | Background & Aims Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown. Methods Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα–/– and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ–/– and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. Results Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c–Ly6G–CD11b+CD68– myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response. Conclusions Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori. Graphical abstract |
| Databáze: | OpenAIRE |
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