Lymphotoxin β receptor signalling executes <i>Helicobacter pylori</i>-driven gastric inflammation in a T4SS-dependent manner.

Abstract

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 <i>Helicobacter pylori-</i>mediated gastric inflammation and pathology. We analysed several ligands and receptors of the alternative NF-κB pathway, RelB, p52 nuclear translocation and target genes in tissue samples of <i>H. pylori</i>-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 <i>H. pylori</i> were assessed in vitro using human gastric cancer cell lines and distinct <i>H. pylori</i> isolates. The effects of blocking or agonistically activating LTβR on gastric pathology during challenge with a human pathogenic <i>H. pylori</i> strain were studied in a mouse model. Among the tested candidates, LT was significantly increased and activated alternative NF-κB signalling was observed in the gastric mucosa of <i>H. pylori</i>-infected patients. <i>H. pylori</i>induced 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 <i>H. pylori-</i>driven gastritis, whereas LTβR activation in gastric epithelial cells of infected mice induced a broadened pro-inflammatory chemokine milieu, resulting in exacerbated pathology. LTβR-triggered activation of alternative NF-κB signalling in gastric epithelial cells executes <i>H. pylori</i>-induced chronic gastritis, representing a novel target to restrict gastric inflammation and pathology elicited by <i>H. pylori</i>, while exclusively targeting canonical NF-κB may aggravate pathology by enhancing the alternative pathway.