Elevated expression of the AIM2 gene in response to Helicobacter pylori along with the decrease of NLRC4 inflammasome is associated with peptic ulcer development

Abstract

Helicobacter Pylori (H. Pylori) cause peptic ulcer disease (PUD), but the inflammasome's role in PUD is not well understood. Therefore this study has investigated inflammasome compartment expression and IL‐1β production in gastritis (G) and peptic ulcer disease. This study was based on gene expression of inflammasome compartments on stomach biopsies of 50 patients with PUD as cases and 50 individuals with gastritis as controls. The expression of NLRC4, ASC, IL‐18, and serum IL‐1β decreased in the PUD group compared to the control group. AIM2 gene expression increased, and NLRP12 gene expression decreased in H. pylori‐seropositive positive (HP+) individuals compared to H. pylori‐seronegative (HP−) individuals. The G‐HP+ subjects had higher serum IL‐1β and AIM2 gene expression than G‐HP− subjects but lower NLRP3 and NLRP12 gene expression. The PUD‐HP+ had lower serum IL‐1β, but higher AIM2 and IL‐18 expression than PUD‐HP−. The PUD‐HP− patients had decreased IL‐18 expression than G‐HP− group. The PUD‐HP+ had lower serum IL‐1β and NLRC4 expression than G‐HP+, while NLRP1 and NLRP3 were higher in expression in PUD‐HP+. The expression of caspase‐1, NLRP3 and NAIP were correlated with IL‐1β and IL‐18. In conclusion, a decrease in NLRC4, IL‐18, ASC genes, and IL‐1β levels in PUD patients compared to gastritis may act in the development of PUD. H. pylori caused AIM2 induction and reduced NLRP12, indicating their contribution to bacterial responses. Decreased NLRC4 expression and IL‐1β protein, together with enhanced NLRP1, and NLRP3 expression, promotes H. pylori to develop peptic ulcers.

Helicobacter pylori infection and inflammasomes

“…Moreover, the HP+ gastritis tissues showed a higher AIM2 gene expression than HP-gastritis tissues, and the same trend was observed in HP+ peptic ulcer disease tissues. 60 H. pylori infection upregulates mRNA and protein level of AIM2 in human and mouse gastric tissue. In H. felis-infected Aim2−/− mice, stomach inflammation was less severe, along with less immune cells infiltration, attenuated proliferation and apoptosis in gastric epithelial cells and immune cells, lower protein levels of caspase-1 and IL-1β, compared with H. felis-infected wild-type mice, which uncovers a pathogenic role for AIM2 inflammasome in H. pylori-induced gastric disease.…”

“…59 And H. pylori-seropositive (HP+) peptic ulcer disease patients had a higher serum IL-18 level together with enhanced NLRP1 and NLRP3 expression compared with H. pylori-seronegative (HP-) individuals, promoting H. pylori to develop peptic ulcers. 60 Meanwhile, statistical analyses from 51 genetic polymorphisms in 310 ethnic Chinese also revealed a strong association between the joint effect of H. pylori infection and the selected polymorphisms in the NLR pathway (CARD8, NLRP3, NLRP12, NLRX1, and caspase-1) and gastric cancer. 61 At present, the known factors that can induce and activate NLRP3 inflammasome in H. pylori infection mainly come from the virulence factors of H. pylori, including CagPAI, VacA, CagA, and Urease B subunit (UreB).…”

“…80 Moreover, with the progression of the disease, the expression of NLRC4 in gastric mucosal tissues from the patients with HP+ peptic ulcer disease was significantly lower than that of with HP+ gastritis, implicating that decreased NLRC4 expression probably promotes H. pylori to develop peptic ulcers. 60 It has been reported that the biphasic activation mechanism for the NAIP/NLRC4 inflammasome requires both Ser533 phosphorylation of NLRC4 and the interaction of NAIP with the flagellin or T3SS protein, which induces NLRC4 conformational changes by recruiting phosphorylated NLRC4 to the complex and that results in inflammasome assembly and caspase-1 activation. 81 However, H. pylori triggered robust NLRC4 Ser533 Phosphorylation but failed to elicit caspase-1 activation, IL-18 secretion, and pyroptosis in mice bone marrow-derived macrophages (BMDMs).…”

NOD-like Receptor Signaling Pathway in Gastrointestinal Inflammatory Diseases and Cancers

“…The NLRs and NLR signaling pathways may also play an important role in the progression of H. pylori-associated gastritis. A study in 2023 on peptic ulcer disease found that the expression of NLRC4, NLRP12, IL-18 and IL-1β decreased significantly in patients of peptic ulcer disease compared with those of only H. pylori-associated gastritis [74].…”

Differential cytokine expression in gastric tissues highlights helicobacter pylori’s role in gastritis

“…The progression of gastritis to gastric cancer is closely linked to the differential expression of various inflammatory cytokines 20 – 22 . Key cytokines identified as playing a crucial role in the development and progression of gastritis include IL-1β, IL-6, IL-8, IL-12, IL-18, and TNF-α 23 – 26 . The roles of these cytokines range from modulating the immune response to directly influencing the inflammatory pathways within the gastric mucosa.…”