Lymphotoxin β receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner

Objective Lymphotoxin beta receptor (LT beta R) signalling has been implicated in inflammation-associated tumour development in different tissues. We have analysed the role of LT beta R and alternative NF-kappa B signalling in Helicobacter pylori-mediated gastric inflammation and pathology. Design We analysed several ligands and receptors of the alternative NF-kappa B pathway, RelB, p52 nuclear translocation and target genes in tissue samples of H. pylori-infected patients with different degrees of gastritis or early gastric tumours by in situ hybridisation, immunohistochemistry, Western blot and real-time PCR analyses. Molecular mechanisms involved in LT beta R activation by H. pylori were assessed in vitro using human gastric cancer cell lines and distinct H. pylori isolates. The effects of blocking or agonistically activating LT beta R on gastric pathology during challenge with a human pathogenic H. pylori strain were studied in a mouse model. Results Among the tested candidates, LT was significantly increased and activated alternative NF-kappa B signalling was observed in the gastric mucosa of H. pylori-infected patients. H. pylori induced LT beta R-ligand expression in a type IV secretion system-dependent but CagA-independent manner, resulting in activation of the alternative NF-kappa B pathway, which was further enhanced by blocking canonical NF-kappa B during infection. Blocking LT beta R signalling in vivo suppressed H. pylori-driven gastritis, whereas LT beta R activation in gastric epithelial cells of infected mice induced a broadened pro-inflammatory chemokine milieu, resulting in exacerbated pathology. Conclusions LT beta R-triggered activation of alternative NF-kappa B signalling in gastric epithelial cells executes H. pyloriinduced chronic gastritis, representing a novel target to restrict gastric inflammation and pathology elicited by H. pylori, while exclusively targeting canonical NF-kappa B may aggravate pathology by enhancing the alternative pathway.