While lung cancer holds the top spot for cancer-causing mortality in the US, the combined mortality attributed to cancers in the digestive diseases, where GI tract cancers account for half of the cases, exceeds that of lung cancer. Chronic inflammation is a shared risk factor for GI tract cancers, which can lead to the development of premalignant lesions (e.g., intestinal metaplasia of the esophagus, stomach, and biliary tract but also colonic dysplasia-associated lesions and mass (DALM) in inflammatory bowel disease (IBD)). Improved understanding of how chronic inflammation develops by generating new knowledge that more precisely defines the mechanisms that lead to cellular infiltration in the GI tract is critical as it opens the door for novel target discovery in treating this condition. In the stomach, the inflammation-intestinal metaplasia-gastric cancer sequence (a.k.a., Correa cascade) is well-established especially in Helicobacter pylori infection but there is currently no effective treatment for chronic gastritis particularly when observed in post-H. pylori eradication or antibiotic refractory H. pylori infection. We proposed a previously unrecognized mechanism of H. pylori gastritis. Our novel data show that Absent In Melanoma 2 (AIM2), a part of the inflammasome that contributes to host defense against bacteria and viruses, is a major regulatory pathway during chronic Helicobacter infection. Because the C-terminal HIN domain of AIM2 binds double-stranded DNA and acts as a cytosolic dsDNA sensor that leads to autoactivation of caspase- 1, an enzyme that processes the proinflammatory cytokine IL-1?, we therefore initially expected AIM2-/- mice to develop less severe Helicobacter gastric pathology. However, our surprising data show that, compared to infected wild-type mice, infected AIM2-/- mice had significantly more gastritis characterized by a significant increase in CD8+ tissue-resident memory T cells (TRM). This suggests that AIM2 ameliorates gastric pathology via a mechanism that is independent of its known inflammasome function. Our related work thus far strongly implicates that Helicobacter-induced AIM2 in B cells suppresses the infiltration of CD8+ TRM by negatively regulating B cell chemokine (CXCL16 and CXCL9) production. Based on our preliminary data in this proposal, we hypothesize that AIM2 induction in gastric B cells regulates Helicobacter-associated gastritis by chemokine (CXCL16 and CXCL9)-mediated retention of CD8+ tissue- resident memory T cell. In this proposal, we will investigate how AIM2 regulates gastric B cell function and maturation, CD8+ TRM retention, and correlate H. pylori pathology to AIM2 mutations in patients. While screening for AIM2 genetic variants may help to predict severe H. pylori complications, completion of the proposed study may also provide novel targets for epithelial inflammation especially conditions that are mediated by TRM such as IBD.
The proposal focuses on understanding a new way that our body controls inflammation caused by our gut bacteria. A protein called AIM2 was found to be highly induced by a stomach pathogen called Helicobacter pylori and our preliminary data indicate that AIM2 is found in B cells and controls the severity of stomach inflammation by suppressing the function of B cells needed to trigger T cell inflammation in the stomach. Understanding this new control of stomach inflammation and how B cells play a role in H. pylori infection will not only provide new knowledge to manage this infection but potentially new treatments for chronic inflammation, a condition that can lead to the development of precancerous lesions both in the gut but also other epithelial surfaces of the body.
