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

BACKGROUND & AIMS: Rev-erb alpha represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erb alpha in Helicobacter pylori infection are presently unknown. METHODS: Rev-erb alpha 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-erb alpha regulation assays. Gastric tissues from Rev-erb alpha(-/-) and wildtype (littermate control) mice or these mice adoptively transferred with CD4(+) T cells from IFN-gamma(-/-) and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erb alpha 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-erb alpha function assays. RESULTS: Rev-erb alpha was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erb alpha via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-kappa B directly binding to Rev-erb alpha promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erb alpha in GECs not only directly suppressed Reg3b and beta-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-erb alpha, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori.

Automated summary

This study reveals the important role of Rev-erb alpha in Helicobacter pylori infection, showing how it affects the host's defense mechanisms against the bacteria through regulation of gastric epithelial cells. The findings shed light on the pathogenesis of H. pylori infection and provide valuable insights into potential therapeutic strategies.