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

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Abstract

Objective

Lymphotoxin β receptor (LTβR) signalling has been implicated in inflammation-associated tumour development in different tissues. We have analysed the role of LTβR and alternative NF-κB signalling in Helicobacter pylori-mediated gastric inflammation and pathology.

Design

We analysed several ligands and receptors of the alternative NF-κB 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 LTβR 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 LTβR 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-κB signalling was observed in the gastric mucosa of H. pylori-infected patients. H. pyloriinduced LTβR–ligand expression in a type IV secretion system-dependent but CagA-independent manner, resulting in activation of the alternative NF-κB pathway, which was further enhanced by blocking canonical NF-κB during infection. Blocking LTβR signalling in vivo suppressed H. pylori-driven gastritis, whereas LTβR activation in gastric epithelial cells of infected mice induced a broadened pro-inflammatory chemokine milieu, resulting in exacerbated pathology.

Conclusions

LTβR-triggered activation of alternative NF-κB signalling in gastric epithelial cells executes H. pylori-induced chronic gastritis, representing a novel target to restrict gastric inflammation and pathology elicited by H. pylori, while exclusively targeting canonical NF-κB may aggravate pathology by enhancing the alternative pathway.

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