Helicobacter urease activates the TLR2/NLRP3/IL-18 axis to protect against asthma

Inflammasome activation and the caspase-1-dependent processing and secretion of IL-1b and IL-18 are critical events at the interface of the bacterial pathogen Helicobacter pylori with its host. Whereas IL-1b promotes Th1 and Th17 responses and gastric immunopathology, IL-18 is required for Treg differentiation, H. pylori persistence and the protection against allergic asthma that 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 TLR2 signaling induced by H. pylori. Screening of an H. pylori transposon mutant library revealed distinct roles for the bacteria’s LPS in proIL-1b expression, and for the urease B subunit in NLRP3 inflammasome licensing (see schematic in Figure). UreB activates the TLR2-dependent expression of NLRP3, which represents a rate-limiting step in NLRP3 inflammasome assembly. UreB gene deletion mutants are defective for caspase-1 activation in murine bone-marrow-derived and splenic DCs as well as human blood-derived DCs. Despite colonizing the murine stomach, ureB mutants fail to induce IL-1b and IL-18 secretion and to promote Treg responses. Unlike wild type H. pylori, ureB mutants are incapable of conferring protection against allergen-induced asthma, indicating a critical contribution of the TLR2/NLRP3/caspase-1/IL-18 axis to H. pylori-specific immune regulation. Further reading: Koch et al. Journal of Clinical Investigation, 2015.

Figure 4

Figure. Schematic of H. pylori-induced inflammasome activation, cytokine processing and downstream effects.

H. pylori LPS and the urease B subunit (UreB) promote NLRP3 inflammasome and caspase-1 activation as well as IL-1b and IL-18 processing and secretion. H. pylori LPS activates IL-1b expression via TLR4, MyD88 and NF-kB (indicated by red arrows), whereas UreB signals via TLR2, MyD88 and NF-kB to activate NLRP3 transcription (green arrows). The assembly of NLRP3, ASC and pro-caspase-1 is triggered through an as yet unknown mechanism, leading to caspase-1 activation and to the processing of pro-IL-1b and pro-IL-18. The mature cytokines are released, bind to their receptors on naive T-cells and promote Th1 differentiation and H. pylori control in the case of IL-1b, and Treg differentiation, immune tolerance and persistence in the case of IL-18. The pro-form of IL-18 is constitutively expressed in DCs.