Helicobacter urease-induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma.

Abstract

Inflammasome activation and caspase-1-dependent (CASP1-dependent) processing and secretion of IL-1β and IL-18 are critical events at the interface of the bacterial pathogen Helicobacter pylori with its host. Whereas IL-1β promotes Th1 and Th17 responses and gastric immunopathology, IL-18 is required for Treg differentiation, H. pylori persistence, and protection against allergic asthma, which is a hallmark of H. pylori-infected mice and humans. Here, we show that inflammasome activation in DCs requires the cytoplasmic sensor NLRP3 as well as induction of TLR2 signaling by H. pylori. Screening of an H. pylori transposon mutant library revealed that pro-IL-1β expression is induced by LPS from H. pylori, while the urease B subunit (UreB) is required for NLRP3 inflammasome licensing. UreB activates the TLR2-dependent expression of NLRP3, which represents a rate-limiting step in NLRP3 inflammasome assembly. ureB-deficient H. pylori mutants were defective for CASP1 activation in murine bone marrow-derived DCs, splenic DCs, and human blood-derived DCs. Despite colonizing the murine stomach, ureB mutants failed to induce IL-1β and IL-18 secretion and to promote Treg responses. Unlike WT H. pylori, ureB mutants were incapable of conferring protection against allergen-induced asthma in murine models. Together, these results indicate that the TLR2/NLRP3/CASP1/IL-18 axis is critical to H. pylori-specific immune regulation.

• Authors: Katrin N Koch, Mara L Hartung, Sabine Urban, Andreas Kyburz, Anna S Bahlmann, Judith Lind, Steffen Backert, Christian Taube, Anne Müller
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 8 Pg. 3297-302 (Aug 03 2015) ISSN: 1558-8238 [Electronic] United States
• PMID: 26214524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• Carrier Proteins
• IL1B protein, mouse
• Inflammasomes
• Intercellular Signaling Peptides and Proteins
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Tlr2 protein, mouse
• Toll-Like Receptor 2
• interleukin-18 binding protein
• Urease

Topics

• Animals
• Asthma (genetics, immunology, prevention & control)
• Bacterial Proteins (genetics, immunology)
• Carrier Proteins (genetics, immunology)
• Dendritic Cells (immunology)
• Gene Expression Regulation (drug effects)
• Helicobacter pylori (genetics, immunology)
• Humans
• Inflammasomes (genetics, immunology)
• Intercellular Signaling Peptides and Proteins (genetics, immunology)
• Interleukin-1beta (genetics, immunology)
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Toll-Like Receptor 2 (genetics, immunology)
• Urease (genetics, immunology)