Participation of the transient receptor potential melastatin 2 ion channel in oxidative stress response and host defense during Helicobacter pylori infection (INM8P.448)

Abstract

Abstract Helicobacter pylori (Hp) is a dominant member of the gastric microbiota in a majority of the world’s population. Hp colonization has been attributed to detrimental outcomes including gastritis and gastric cancer. The immune response to Hp leads to elevated levels of reactive oxygen species and reactive nitrogen species within the gastric mucosa. The redox-sensitive cation channel TRPM2 is activated by direct binding of ADP ribose and under conditions of oxidative and metabolic stress by H2O2 and H+. TRPM2 is strongly expressed in immune cells of the phagocytic lineage, themselves professional oxidants-generators. Here we report that Hp infection of TRPM2-deficient macrophages resulted in higher rates of bacterial killing and increased levels of proinflammatory cytokines and NOX2 compared to wild-type macrophages. Consequently, TRPM2-deficient macrophages displayed significantly higher ROS production during Hp infection, suggesting an increased NADPH oxidase activity. In vivo, when TRPM2-deficient mice were infected orogastrically with Hp their gastric tissues exhibited an increased NOX2 expression and myeloperoxidase activity compared to wild-type mice. Furthermore, enhancement of NADPH oxidase activity in TRPM2-deficient animals increased inflammation and reduced bacterial burden when compared with wild-type mice. Taken together, these data indicate that TRPM2 establishes a negative feedback of ROS production through phagosomal NADPH oxidase during Hp infection.