Oxygen sensing in intestinal mucosal inflammation

Abstract

Hypoxia is a hallmark of chronically inflamed tissue. Hypoxia develops from vascular dysfunction and increased oxygen consumption by infiltrating leukocytes. With respect to inflammatory bowel disease (IBD), hypoxia is likely to be of particular importance: Impairment of the intestinal barrier during IBD allows anoxia from the lumen of the gut to spread to formerly normoxic tissue. In addition, disturbed perfusion of inflamed tissue and a higher oxygen demand of infiltrating immune cells lead to low oxygen levels in inflamed mucosal tissue. Here, cells become hypoxic and must now adapt to this condition. The hypoxia inducible factor (HIF)-1 complex is a key transcription factor for cellular adaption to low oxygen tension. HIF-1 is a heterodimer formed by two subunits: HIF-α (either HIF-1α or HIF-2α) and HIF-1β. Under normoxic conditions, hydroxylation of the HIF-α subunit by specific oxygen-dependent prolyl hydroxylases (PHDs) leads to ubiquitin proteasome-dependent degradation. Under hypoxic conditions, however, PHD activity is inhibited; thus, HIF-α can translocate into the nucleus, dimerize with HIF-1β, and bind to hypoxia-responsive elements of HIF-1 target genes. So far, most studies have addressed the function of HIF-1α in intestinal epithelial cells and the effect of HIF stabilization by PHD inhibitors in murine models of colitis. Furthermore, the role of HIF-1α in immune cells becomes more and more important as T cells or dendritic cells for which HIF-1 is of critical importance are highly involved in the pathogenesis of IBD. This review will summarize the function of HIF-1α and the therapeutic prospects for targeting the HIF pathway in intestinal mucosal inflammation.

Bacteria-mediated hypoxia functions as a signal for mosquito development

“…In contrast, PHD hydroxylation does not occur under hypoxia, which stabilizes HIF-α/β to activate hypoxia-responsive genes (33). FG-4592 is an oral inhibitor of HIF PHDs that stabilizes HIF-α/β and triggers a hypoxia transcriptional program under normoxic conditions (35)(36)(37). Transcriptional profiling indicated that Ae.…”

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…In addition, infiltrating neutrophils at sites of inflammation contribute to hypoxia, as these cells require high levels of oxygen to support the oxidative burst that is used as an endogenous antimicrobial strategy (8,9). Reduced oxygenation of inflamed tissues is of particular relevance in chronic inflammatory diseases of the intestine, such as inflammatory bowel disease, where the development of thrombosis, fibrosis, and associated vascular dysfunction often leads to diminished tissue perfusion (10,11). Therefore, hypoxia is a common feature of the microenvironment of chronically inflamed tissues.…”

The role of HIF in immunity and inflammation

“…Another cause of hypoxia during inflammation is disrupted oxygen delivery. This is particularly the case in chronic inflammation where the combination of prolonged inflammatory activity and associated fibrosis and thrombosis results in diminished blood (and consequently oxygen) supply to the site of inflammation [11]. Therefore, a combination of increased oxygen consumption by inflamed resident cells and infiltrating immune cells along with a disrupted blood supply due to vascular dysfunction contributes to tissue hypoxia during chronic inflammation ( Figure 1).…”