Unveiling the Crucial Role of Type IV Secretion System and Motility of Helicobacter pylori in IL-1β Production via NLRP3 Inflammasome Activation in Neutrophils

Abstract

<i>Helicobacter pylori</i> is a gram-negative, microaerophilic, and spiral-shaped bacterium and causes gastrointestinal diseases in human. IL-1β 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-1β production by neutrophils during <i>H. pylori</i> infection is still unknown. We designed this study to identify host and bacterial factors involved in regulation of <i>H. pylori</i>-induced IL-1β production in neutrophils. We found that <i>H. pylori</i>-induced IL-1β production is abolished in NLRP3-, ASC-, and caspase-1/11-deficient neutrophils, suggesting essential role for NLRP3 inflammasome in IL-1β response against <i>H. pylori</i>. Host TLR2, but not TLR4 and Nod2, was also required for transcription of NLRP3 and IL-1β as well as secretion of IL-1β. <i>H. pylori</i> lacking <i>cagL</i>, a key component of the type IV secretion system (T4SS), induced less IL-1β production in neutrophils than did its isogenic WT strain, whereas <i>vacA</i> and <i>ureA</i> were dispensable. Moreover, T4SS was involved in caspase-1 activation and IL-1β maturation in <i>H. pylori</i>-infected neutrophils. We also found that FlaA is essential for <i>H. pylori</i>-mediated IL-1β production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required for <i>H. pylori</i>-induced IL-1β production in neutrophils. Instead, bacterial motility is essential for the production of IL-1β in response to <i>H. pylori</i>. In conclusion, our study shows that host TLR2 and NLRP3 inflammasome and bacterial T4SS and motility are essential factors for IL-1β production by neutrophils in response to <i>H. pylori</i>.