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

Helicobacter pylori 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 H. pylori infection is still unknown. We designed this study to identify host and bacterial factors involved in regulation of H. pylori-induced IL-1β production in neutrophils. We found that H. pylori-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 H. pylori. Host TLR2, but not TLR4 and Nod2, was also required for transcription of NLRP3 and IL-1β as well as secretion of IL-1β. H. pylori lacking cagL, a key component of the type IV secretion system (T4SS), induced less IL-1β 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-1β maturation in H. pylori-infected neutrophils. We also found that FlaA is essential for H. pylori-mediated IL-1β production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required for H. pylori-induced IL-1β production in neutrophils. Instead, bacterial motility is essential for the production of IL-1β 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-1β production by neutrophils in response to H. pylori.

Innate Immune Responses in Pediatric Patients with Gastritis—A Trademark of Infection or Chronic Inflammation?

“…Perez-Figueroa et al proved that H. pylori could increase the expression of NLRP3 inflammasome components, while the inhibitors of this inflammasome and caspase-1 induce a reduction in IL-1β production [ 6 ]. In addition, a strong partnership was noted between NLRP3 and TLR2 regarding the production of this interleukin since, according to Jang et al, this TLR is essential for the production of H. pylori -induced IL-1β in neutrophils [ 14 ]. The same authors noticed a reduction in the expression of both NLRP3 and IL-1β genes in TLR2-deficient neutrophils.…”

“…Nevertheless, NLRP3 inflammasome remains the most important host factor in neutrophils that promotes the production of IL-1β in response to H. pylori infection since both the secretion and cleavage of this interleukin were abolished in NLRP3- and caspase-1/11-deficient neutrophils [ 14 ]. Neutrophils were defined as crucial innate immune cells in H. pylori -mediated gastric inflammation [ 37 ].…”

“…Based on our findings, we might define a trialogue between TLR2, NLRP3, and neutrophils in developing subclinical inflammation related to H. pylori infection in children, which might represent an early leading cause for gastric carcinogenesis. Moreover, both bacterial and host factors were proven to have a synergistic role in the production of IL-1β in neutrophils [ 14 ].…”

“…Contrariwise, studies reported that the inhibition of caspase-1, a crucial player in the maturation of IL-1β and IL-18, reduces gastric inflammation by blocking the NLRP3 inflammasome pathway [ 13 ]. The activation of NLRP3 is a two-step process, consisting initially in the transcription of pro-IL-1β and NLRP3 as a result of NF-kB and AP-1 activation by pattern-recognition receptors (PRRs) in response to microbial stimuli, and secondly in the oligomerization of NLRP3 inflammasome, activation of caspase-1 and pro-IL-1β cleavage by caspase-1, and finally the secretion of mature IL-1β [ 14 , 15 ].…”

The role of toll-like receptors in peptic ulcer disease

“…However, additional experiments are needed because factors that affect preformed NLRP3 and pro-caspase-1 are difficult to identify. Furthermore, the most recent study presents that TLR2 and the NLRP3 inflammasome are also important because they influence the production of IL-1b by neutrophils in response to T4SS and flagellin [65]. On the contrary, further consideration is required, as other signaling pathways might also regulate IL-1b production by neutrophils.…”