Unveiling the Crucial Role of Type IV Secretion System and Motility ofHelicobacter pyloriin IL-1 beta Production via NLRP3 Inflammasome Activation in Neutrophils

Abstract

Helicobacter pyloriis 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 duringH. pyloriinfection is still unknown. We designed this study to identify host and bacterial factors involved in regulation ofH. pylori-induced IL-1 beta production in neutrophils. We found thatH. 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 againstH. 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. pylorilackingcagL, a key component of the type IV secretion system (T4SS), induced less IL-1 beta production in neutrophils than did its isogenic WT strain, whereasvacAandureAwere dispensable. Moreover, T4SS was involved in caspase-1 activation and IL-1 beta maturation inH. pylori-infected neutrophils. We also found that FlaA is essential forH. pylori-mediated IL-1 beta production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required forH. pylori-induced IL-1 beta production in neutrophils. Instead, bacterial motility is essential for the production of IL-1 beta in response toH. 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 toH. pylori.