Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori-induced gastric injury via attenuation of both cag-mediated microbial virulence and proinflammatory host responses

Noto, Jennifer M.; Piazuelo, M. Blanca; Romero-Gallo, Judith; Delgado, Alberto G.; Suarez, Giovanni; Akritidou, Konstantina; Hoffman, Miguel Girod; Roa, Juan Carlos; Taylor, Cormac T.; Peek, Richard M., Jr.

Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori-induced gastric injury via attenuation of both cag-mediated microbial virulence and proinflammatory host responses

Date

2023

Authors

Akritidou, Konstantina

Hoffman, Miguel Girod

Roa, Juan Carlos

Taylor, Cormac T.

Peek, Richard M., Jr.

Abstract

Helicobacter pylori-induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1 alpha) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori-induced injury, we first demonstrated that HIF-1 alpha levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1 alpha, H. pylori-infected mice were treated +/- dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1 alpha. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-kappa B activation and IL-8 induction in vitro. These results suggest that prolyl hydroxylase inhibition protects against H. pylori-mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag-mediated virulence and suppression of host proinflammatory responses.

Keywords

Helicobacter pylori, gastric inflammation, gastric cancer, hypoxia-inducible factor-1 alpha (HIF-1 alpha), dimethyloxalylglycine (DMOG), prolyl hydroxylase (PHD)