Oxygen metabolism and innate immune responses in the gut

Epithelial cells of the mucosa provide a first line of defense to prevent the inappropriate translocation of luminal antigens, and therefore contribute significantly to nonspecific innate immunity. In the gastrointestinal (GI) tract, barrier is provided by multiple components of the mucosa, including mucus production, epithelial junctional complexes, and the production of antimicrobial molecules. In recent years, it is better appreciated that tissue oxygen metabolism is key to homeostasis in the mucosa. The intestine, for example, maintains a low baseline Po₂ level due to high rates of metabolism, countercurrent blood flow, and the presence of a steep oxygen gradient across the luminal aspect of tissue surface. As a result, hypoxia and hypoxia-inducible factor (HIF)-dependent signaling exists even in the healthy, unperturbed intestinal mucosa. In a number of examples, HIF has been demonstrated both to promote barrier function during homeostasis and to promote resolution of active inflammation. Hypoxia-elicited factors that contribute to innate responses in the mucosa include the transcriptional regulation of mucin genes, junction proteins, and autophagic flux. Here, we review current literature related to hypoxia and innate immunity in health and during mucosal inflammation.