NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori‐infected gastric epithelial cells

Abstract

The accumulation of Helicobacter pylori infection‐ induced DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer; however, the underlying mechanisms remain poorly understood. Here we report that suppression of the DNA repair enzyme NEIL2 is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of gastric cancers (GCs). We found that NEIL2 was significantly downregulated upon H. pylori infection both in vitro and in human gastric biopsies. The H. pylori infection‐induced downregulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine and human stomach in co‐culture studies with live microbes, mimicking the infected stomach lining, we found that H. pylori infection was associated with proinflammatory cytokines release; this response was more pronounced in Neil2 knock out (KO) mouse cells compared to wild type (WT) cells suggesting that NEIL2 suppresses inflammation under physiological conditions. In vivo studies in mice showed that despite a lower bacterial load, as determined by UreB expression, DNA damage was significantly higher in Neil2 KO mice compared to WT mice. Interestingly, after infection with H. pylori, Neil2 KO mice has higher inflammation and epithelial cell damage compared to WT cells. Taken together, our data suggest that downregulation of NEIL2 is a plausible way of how H. pylori infection derails DNA damage repair mechanisms and initiates GCs.Support or Funding InformationThis work was supported, in whole or in part, by National Institute of Health Grants: DK107585 and DK099275 (to SD); R01 NS073976 (to TH).