Stabilization but No Functional Influence of HIF-1α Expression in the Intestinal Epithelium during Salmonella Typhimurium Infection

Hypoxia-inducible transcription factor 1 (HIF-1) has been shown to enhance microbial killing and ameliorate the course of bacterial infections. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the gastrointestinal tract remains largely elusive. With the help of a publicly available gene expression data set, we inferred significant activation of HIF-1 after oral infection of mice with Salmonella enterica serovar Typhimurium. Immunohistochemistry and Western blot analyses confirmed marked HIF-1 alpha protein stabilization, especially in the intestinal epithelium. This prompted us to analyze conditional Hif1a-deficient mice to examine cell type-specific functions of HIF-1 in this model. Our results demonstrate enhanced noncanonical induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells did not impact inflammatory gene expression, bacterial spread, or disease outcomes. In contrast, Hif1a deletion in myeloid cells enhanced intestinal Cxcl2 expression and reduced the cecal Salmonella load. In vitro, HIF-1 alpha-deficient macrophages showed overall impaired transcription of mRNA encoding proinflammatory factors; however, the intracellular survival of Salmonella was not impacted by HIF-1 alpha deficiency.

Automated summary

HIF-1 plays an important role in bacterial infections of the gastrointestinal tract. However, its function varies in intestinal epithelial cells and macrophages. Deletion of Hif1a in intestinal epithelial cells does not affect inflammatory gene expression or bacterial spread, whereas deletion of Hif1a in myeloid cells enhances the inflammatory response and reduces bacterial load in the intestines.