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

Abstract

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. 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 gastric cancer. We therefore investigated whether AIM2 contributed to the pathogenesis of Helicobacter-induced gastric disease. Here, we reveal that AIM2 messenger RNA and protein expression levels are elevated in H. pylori-positive versus H. pylori-negative human gastric biopsies. Similarly, chronic Helicobacter felis infection in wild-type mice augmented Aim2 gene expression levels compared with uninfected controls. Notably, gastric inflammation and hyperplasia were less severe in H. felis-infected Aim2 À/À versus wild-type mice, evidenced by reductions in gastric immune cell infiltrates, mucosal thickness and proinflammatory cytokine and chemokine release. In addition, H. felisdriven proliferation and apoptosis in both gastric epithelial and immune cells were largely attenuated in Aim2 À/À stomachs. These observations in Aim2 À/À mouse stomachs correlated with decreased levels of inflammasome activity (caspase-1 cleavage) and the mature inflammasome effector cytokine, interleukin-1b. 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 precancerous gastric disease.

Absent in Melanoma 2 Mediates Inflammasome Signaling Activation against Clostridium perfringens Infection

“…As a novel member of the interferon-induced PYHIN proteins, AIM2 plays a significant role in regulating innate immunity [ 23 ]. Recently, numerous studies, including ours, have shown that AIM2 is associated with pathogenic infections [ 24 , 25 , 26 ]. However, the role of AIM2 in pathogenic C .…”