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Lymphotoxin β receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner
  1. Raquel Mejías-Luque1,2,
  2. Jessica Zöller3,
  3. Florian Anderl1,
  4. Elena Loew-Gil1,
  5. Michael Vieth4,
  6. Thure Adler5,
  7. Daniela B Engler6,
  8. Sabine Urban6,
  9. Jeffrey L Browning7,
  10. Anne Müller6,
  11. Markus Gerhard1,2,
  12. Mathias Heikenwalder3,8
  1. 1Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
  2. 2German Centre for Infection Research (DZIF), partner site Munich, Munich, Germany
  3. 3Institut für Virologie, Technische Universität München, Helmholtz Zentrum München, Neuherberg, Germany
  4. 4Institut für Pathologie, Klinikum Bayreuth, Bayreuth, Germany
  5. 5Immunology Screen, German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany
  6. 6Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
  7. 7Department of Immunobiology, Biogen Idec, Cambridge, Massachusetts, USA
  8. 8Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  1. Correspondence to Professor Mathias Heikenwälder, Schneckenburgerstrasse 8, Munich 81675, Germany; heikenwaelder{at}helmholtz-muenchen.de, mheikenwaelder{at}dkfz.de Division of Chronic Inflammation and Cancer (German Cancer Research Center) DKFZ, or Professor Markus Gerhard, Trogerstrasse 30, Munich, 81675, Germany; markus.gerhard{at}tum.de, Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Germany

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.

  • HELICOBACTER PYLORI - PATHOGENESIS
  • HELICOBACTER PYLORI - GASTRITIS
  • EPITHELIAL CELLS

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