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

<p dir="ltr">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.</p><p dir="ltr">Methods: Rev-erbα was examined in gastric samples from <i>H pylori</i>-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with <i>H pylori</i> for Rev-erbα regulation assays. Gastric tissues from <i>Rev-erbα</i>^–/– and wild-type (littermate control) mice or these mice adoptively transferred with CD4⁺ T cells from <i>IFN-γ</i>^–/– and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/bacterial-colonization" target="_blank">bacteria colonization</a>. GECs, CD45⁺<a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/cd11c" target="_blank">CD11c</a>^–Ly6G^–CD11b⁺<a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/chlordane" target="_blank">CD68</a>^– myeloid cells and CD4⁺ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays.</p><p dir="ltr">Results: Rev-erbα was increased in <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/gastric-mucosa" target="_blank">gastric mucosa</a> of <i>H pylori</i>-infected patients and mice. <i>H pylori</i> induced GECs to express Rev-erbα via the phosphorylated <i>cagA</i> that activated <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/mitogen-activated-protein-kinase" target="_blank">ERK</a> <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/signal-transduction" target="_blank">signaling pathway</a> to mediate NF-κB directly binding to <i>Rev-erbα</i> promoter, which resulted in increased bacteria colonization within <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/stomach-mucosa" target="_blank">gastric mucosa</a>. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/bactericidal-activity" target="_blank">bactericidal effects</a> against <i>H pylori</i> of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/ccl21" target="_blank">CCL21</a> expression, which led to decreased gastric influx of CD45⁺CD11c^–Ly6G^–CD11b⁺<a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/cd68" target="_blank">CD68</a>^– myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of <i>H pylori</i>-specific Th1 cell response.</p><p dir="ltr">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 <i>H pylori</i>.</p><p dir="ltr"><br></p>