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bioRxiv · 10.1101/733790

Unveiling the crucial role of type IV secretion system and motility of Helicobacter pylori in IL-1β production via NLRP3 inflammasome activation in neutrophils

Jang, A.-R.·Kang, M.-J.·Shin, J.-I.·Kwon, S.-W.·Park, J.-Y.·Ahn, J.-H.·Lee, T.-S.·Kim, D.-Y.·Choi, B.-G.·Seo, M.-W.·Yang, S.-J.·Shin, M.-K.·Park, J.-H.
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Abstract

Helicobacter pylori is a gram-negative, microaerophilic, and spiral-shaped bacterium and causes gastrointestinal diseases in human. IL-1{beta} is a representative cytokine produced in innate immune cells and is considered to be a key factor in the development of gastrointestinal malignancies. However, the mechanism of IL-1{beta} production by neutrophils during H. pylori infection is still unknown. We designed this study to identify host and bacterial factors involved in regulation of H. pylori-induced IL-1{beta} production in neutrophils. We found that H. pylori-induced IL-1{beta} production is abolished in NLRP3-, ASC-, and caspase-1/11-deficient neutrophils, suggesting essential role for NLRP3 inflammasome in IL-1{beta} response against H. pylori. Host TLR2, but not TLR4 and Nod2, was also required for transcription of NLRP3 and IL-1{beta} as well as secretion of IL-1{beta}. H. pylori lacking cagL, a key component of the type IV secretion system (T4SS), induced less IL-1{beta} production in neutrophils than did its isogenic WT strain, whereas vacA and ureA were dispensable. Moreover, T4SS was involved in caspase-1 activation and IL-1{beta} maturation in H. pylori-infected neutrophils. We also found that FlaA is essential for H. pylori-mediated IL-1{beta} production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required for H. pylori-induced IL-1{beta} production in neutrophils. Instead, bacterial motility is essential for the production of IL-1{beta} in response to H. pylori. In conclusion, our study shows that host TLR2 and NLRP3 inflammasome and bacterial T4SS and motility are essential factors for IL-1{beta} production by neutrophils in response to H. pylori.\n\nIMPORTANCEIL-1{beta} is a representative pro-inflammatory cytokine and is considered to be a central host factor for the development of gastric cancers. Although neutrophils have been considered to be involved in H. pylori-induced gastric inflammation, the underlying mechanism by which H. pylori triggers IL-1{beta} production in neutrophils remains to be defined. In this study, our data suggested a critical role for the host TLR2 and NLRP3 inflammasome in IL-1{beta} production by neutrophil during H. pylori infection. Moreover, we found the bacterial factors, T4SS and FlaA, to be essential for IL-1{beta} production and NLRP3 activation during the course of H. pylori infection. Our current findings provide detailed molecular genetic mechanisms associated with IL-1{beta} production in neutrophils in response to H. pylori infection, which can serve as innovative anti-inflammatory targets to reduce H. pylori-induced gastric malignancies.

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Jang, A.-R., Kang, M.-J., Shin, J.-I., Kwon, S.-W., Park, J.-Y., Ahn, J.-H., Lee, T.-S., Kim, D.-Y., Choi, B.-G., Seo, M.-W., Yang, S.-J., Shin, M.-K., Park, J.-H.. 2019-08-13. Unveiling the crucial role of type IV secretion system and motility of Helicobacter pylori in IL-1β production via NLRP3 inflammasome activation in neutrophils. https://doi.org/10.1101/733790

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