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The cytosolic DNA sensor AIM2 promotes Helicobacter-induced gastric pathology via the inflammasome.

Ruby E DawsonVirginie DeswaerteAlison C WestEkimei SunGeorgie Wray-McCannThaleia LivisBeena KumarEmiliana RodriguezCem GabayRichard L FerreroBrendan J Jenkins
Published in: Immunology and cell biology (2023)
Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer (GC). However, key regulators of innate immunity that promote H. pylori-induced gastric pathology remain ill-defined. The innate immune cytosolic DNA sensor Absent In Melanoma 2 (AIM2) contributes to the pathogenesis of numerous autoimmune and chronic inflammatory diseases, as well as cancers including GC. We therefore investigated whether AIM2 contributed to the pathogenesis of Helicobacter-induced gastric disease. Here, we reveal that AIM2 mRNA and protein expression levels are elevated in H. pylori-positive versus H. pylori-negative human gastric biopsies. Similarly, chronic H. felis infection in wild-type mice augmented Aim2 gene expression levels compared to uninfected controls. Notably, gastric inflammation and hyperplasia were less severe in H. felis-infected Aim2 -/- versus wild-type mice, evidenced by reductions in gastric immune cell infiltrates, mucosal thickness and pro-inflammatory cytokine and chemokine release. Additionally, H. felis-driven proliferation and apoptosis in both gastric epithelial and immune cells were largely attenuated in Aim2 -/- stomachs. These observations in Aim2 -/- mouse stomachs correlated with decreased levels of inflammasome activity (Caspase-1 cleavage) and the mature inflammasome effector cytokine, interleukin-1β. Taken together, this work uncovers a pathogenic role for the AIM2 inflammasome in Helicobacter-induced gastric disease, and furthers our understanding of the host immune response to a common pathogen and the complex and varying roles of AIM2 at different stages of cancerous and pre-cancerous gastric disease.
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