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  • Helicobacter pylori-Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense.

Helicobacter pylori-Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense.

Cellular and molecular gastroenterology and hepatology (2021-03-07)
Fang-Yuan Mao, Yi-Pin Lv, Chuan-Jie Hao, Yong-Sheng Teng, Yu-Gang Liu, Ping Cheng, Shi-Ming Yang, Weisan Chen, Tao Liu, Quan-Ming Zou, Rui Xie, Jing-Yu Xu, Yuan Zhuang
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
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