In the presence of oxygen, prolyl hydrolyases (PHD) modify the alpha subunits at two prolines, leading to polyubiquitylation and proteasomal degradation. The activity of this system is regulated by the posttranslational modification and stability of the alpha subunits (HIF-1α or HIF-2α) of the transcription factor complex. Hypoxia-Inducible Factor (HIF) Signaling and T CellsĬells sense and adapt to hypoxia in part through the well-described HIF signaling pathway ( 11). Examining the role of hypoxia in modulating epithelial cell and immune cell responses has been an area of active investigation in the design of new therapeutics for treating IBD ( 10). In the GI tract, mice with experimental models of inflammatory bowel disease (IBD) have increased inflammation and decreased oxygen levels in their colonic tissues ( 8), which corresponds with pathology observed in IBD patients ( 9). In patients, many different inflamed tissues have been shown to have lower than normal oxygen levels. Inflammation and environmental oxygen levels are linked inflammation is often accompanied by hypoxia, and hypoxia itself can cause inflammation ( 7). These oxygen levels can be further modulated within the cell’s microenvironment. A progenitor or mature T cell may be exposed an oxygen concentration between 3 and 19% oxygen. T cells begin life in the bone marrow progenitors migrate to the thymus for development, then to the blood to either circulate through the blood or lymphatic systems or to become a tissue-resident T cell, in such various organs as the lung, skin, brain, or GI tract. Immune cells encounter a wide range of oxygen levels as they traffic within the human body ( 2). The intestinal tissue, including the lamina propria where many T cells reside, is approximately 7% oxygen (58 mmHg) ( 2). The lumen, with its many obligate anaerobic commensal bacteria, is close to 0% oxygen ( 6). The gastrointestinal (GI) tract, which contains upwards of 70–80% of one’s total lymphocytes ( 4), has an especially dynamic oxygen range ( 5). Lymphoid tissues are lower in oxygen bone marrow is approximately 6.4% (50 mmHg) ( 2) and the spleen can range from 3 to 4% (25–35 mmHg) ( 3). The tissues closest to atmospheric oxygen levels (21.1% or 160 mmHg at sea level) are those of the upper airways (approximately 19%, 150 mmHg) ( 2). Oxygen levels vary between 0 and 19% in healthy mammalian tissues. Oxygen Dynamics in Immune Homeostasis and Inflammation As such, T cells have a distinct relationship with oxygen and modulate their function in response to environmental oxygen levels. However, like tumor cells, activated T cells are able to undergo glycolysis even in the presence of oxygen, a process termed aerobic glycolysis ( 1). In most cells, glycolysis is reserved for when oxygen is limited. In contrast, glycolysis is less fuel efficient but can proceed in the absence of oxygen. Oxygen is essential for oxidative phosphorylation, the metabolic pathway in which energy is generated through the electron transport chain in mitochondria. Cells are able to sense oxygen levels and modulate their biosynthetic and transcriptional pathways accordingly.Ĭells have two major pathways for generating energy from a carbon source: oxidative phosphorylation or glycolysis. Related to nutrients is oxygen, which is critical for most multicellular life as an essential element of several biochemical pathways for the generation of cellular energy. Recent studies in immunometabolism have identified nutrient availability (i.e., glucose or other carbon sources, amino acids, lipids) as an important environmental cue, especially in activated, highly metabolic immune cells ( 1). This provides immune cells instruction on how to respond to different inflammatory situations. Cells sense their environment in part through recognition of small molecules such as cytokines, chemokines, and pathogen-associated molecular pattern (PAMP) molecules. Environmental cues are a major component of directing immune function in health and disease.
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