Helicobacter Pylori-Induced Rev-Erb Alpha 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.