Helicobacter pylori-induced Rev-erbα fosters gastric bacterial colonization by impairing host innate and adaptive defense

Background: Helicobacter pylori (H. pylori) is a human pathogen that infects nearly half of the world’s population, however, the persistent colonization of H. pylori in gastric mucosa remains poorly understood. Nowadays it is believed that impairment of host defense of gastric epithelium induced by H. pylori plays key roles in H. pylori-associated pathology. The nuclear receptor Rev-erbα represents a powerful transcriptional repressor involved in host immunity. However, the regulation, function, and clinical relevance of Rev-erbα in H. pylori infection are presently unknown. Here we demonstrated a pro-colonization role of Rev-erbα in H. pylori infection.Results: Rev-erbα was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced gastric epithelial cells (GECs) to express Rev-erbα via the phosphorylated cagA that activated extracellular signal-regulated kinase (ERK) signaling pathway to mediate transcription factor nuclear factor kappa-B (NF-κB) directly binding to Rev-erbα promoter. Human gastric Rev-erbα expression correlated with H. pylori colonization, and mouse Rev-erbα from non-bone marrow-derived cells promoted gastric H. pylori burden. Importantly, H. pylori colonization was attenuated in Rev-erbα-/- mice and the mice with in vivo pharmacological inhibition of Rev-erbα. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression via binding to Reg3b and β-defensin-1 promoter respectively, 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 via binding to CCL21 promoter, 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 T helper type 1 (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, and also highlight a pathological role and an immunosuppressive mechanism of Rev-erbα in persistent H. pylori infection.