Notch Signaling Aggravates Helicobacter pylori-Induced Inflammation by Promoting Macrophage Activation and Proinflammatory Th1/Th17 Responses.

Abstract

The role of Notch signaling in regulating the immune response in infectious and inflammatory diseases has been extensively reported. However, its specific involvement in Helicobacter pylori infection is yet to be fully understood. In this study, in vitro analysis utilizing real-time quantitative PCR and Western blot revealed that H. pylori triggers the activation of Notch signaling in murine bone marrow-derived macrophages (BMDMs) and co-cultured CD4⁺ T cells, a process mediated by the Notch ligand protein jagged-1 (Jag1). There was a reciprocal enhancement between Jag1-Notch signaling and NF-κB pathway in H. pylori-infected macrophages. Pretreatment with a Notch signaling inhibitor, DAPT, reduced the expression of inflammatory mediators in macrophages, modulated their phenotype, and inhibited Th1 differentiation. In vivo, after treatment with DAPT in H. pylori-infected mice, the differentiation of Th1 and Th17 was decreased on flow cytometry analysis. Hematoxylin and eosin staining revealed reduced gastric mucosa inflammation, and enzyme-linked immunosorbent assay results demonstrated decreased levels of serum inflammatory cytokines. Furthermore, the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) results showed that DAPT treatment improved the apoptosis of gastric mucosal cells. Collectively, the findings indicate that Notch signaling is implicated in exacerbating H. pylori-induced inflammation by promoting macrophage activation and Th1/Th17 responses, highlighting its potential as a therapeutic target for alleviating the progression of H. pylori-related diseases.