This information is current as Mediated Gastritis − pylori Helicobacter Myeloid HIF-1 Is Protective in Eliette Touati and

Helicobacter pylori infection triggers chronic inflammation of the gastric mucosa that may progress to gastric cancer. The hypoxia-inducible factors (HIFs) are the central mediators of cellular adaptation to low oxygen levels (hypoxia), but they have emerged recently as major transcriptional regulators of immunity and inflammation. No studies have investigated whether H. pylori affects HIF signaling in immune cells and a potential role for HIF in H. pylori–mediated gastritis. HIF-1 and HIF-2 expression was examined in human H. pylori–positive gastritis biopsies. Subsequent experiments were performed in naive and polarized bone marrow–derived macrophages from wild-type (WT) and myeloid HIF-1a–null mice (HIF-1 Dmyel). WT and HIF-1 Dmyel mice were inoculated with H. pylori by oral gavage and sacrificed 6 mo postinfection. HIF-1 was specifically expressed in macrophages of human H. pylori–positive gastritis biopsies. Macrophage HIF-1 strongly contributed to the induction of proinflammatory genes (IL-6, IL-1b) and inducible NO synthase in response to H. pylori. HIF-2 expression and markers of M2 macrophage differentiation were decreased in response to H. pylori. HIF-1 Dmyel mice inoculated with H. pylori for 6 mo presented with a similar bacterial colonization than WT mice but, surprisingly, a global increase of inflammation, leading to a worsening of the gastritis, measured by an increased epithelial cell proliferation. In conclusion, myeloid HIF-1 is protective in H. pylori–mediated gastritis, pointing to the complex counterbalancing roles of innate immune and inflammatory phenotypes in driving this pathology. I nfection by Helicobacter pylori is the most common chronic bacterial infection of humans, affecting half the population worldwide. Persistent colonization of the gastric mucosa by H. pylori leads to chronic gastric inflammation, which may progress to peptic ulcer disease, gastric cancer, or MALT lym-phoma (1). H. pylori infection is a major determinant initiating the sequence of events leading to gastric cancer, in combination with host and environmental factors. By recruiting immune cells, the bacterium triggers chronic inflammation of the gastric mucosa, and depletion of macrophages has been shown to reduce gastric pathology in H. pylori–infected mice (2), emphasizing a key role for macrophages in this process. Macrophages have multiple functions ranging from host defense, tissue repair, to inflammatory regulation (3), but their mechanistic role in H. pylori disease remains poorly understood. Macrophages exhibit remarkable developmental and functional plasticity, with classically activated macrophages (M1) representing one extreme— the proinflammatory state—and alternatively activated macrophages (M2) representing the opposite anti-inflammatory state. Generally, the M1–M2 switch observed during the transition from …