The balance of oxygen in our bodies is crucial for immune responses. Physiological oxygenation, or physioxia, is vital in how immune cells operate during tissue homeostasis, inflammation, infections, and cancer. In contrast, disease-associated hypoxia occurs when oxygen supply falls short of cellular demands, leading to compromised immune functions.
Here’s how oxygen dynamics influence immunity at the molecular level:
Tissue Homeostasis: Different tissues have varying oxygen levels essential for maintaining immune cell activity. For instance, bone marrow is hypoxic, while lungs are well-oxygenated. Immune cells must adapt to these gradients, utilizing pathways like HIF (hypoxia-inducible factor) to regulate metabolism and function as they migrate through different environments.
Inflammation: Increased cellular activity during inflammation can deplete oxygen levels, impairing immune cell function. Hypoxia can disrupt cytokine production; for example, reduced levels of IFNα—a critical cytokine for antiviral responses—can occur due to HIF-mediated repression of its synthesis. This impairment can alter the balance of pro-inflammatory and anti-inflammatory cytokines, affecting the overall immune response.
Infection: Adequate oxygen is crucial for the efficacy of immune cells. Hypoxic conditions hinder the recruitment and activation of key immune cells like T cells and macrophages. In inflamed tissues, immune cells compete for oxygen and nutrients, leading to increased production of ROS (reactive oxygen species), which can further impair immune responses and promote cellular dysfunction.
Cancer: Tumors often exist in hypoxic environments, which can alter immune cell recruitment and function. Hypoxia promotes the secretion of chemokines that attract immune cells, but these cells usually exhibit reduced functionality due to the modified tumor microenvironment. Additionally, hypoxic tumor cells can upregulate PD-L1, a protein that inhibits T-cell activity, contributing to immune evasion. Manipulating oxygen levels within tumors may enhance treatments like radiotherapy and engineered immune cell therapies by restoring immune cell function.
Disease Immunotherapy: Targeting oxygen-sensing pathways, such as those mediated by HIF, can improve the outcomes of immunotherapies. Strategies may include enhancing autophagy to clear damaged components that provoke inflammation or optimizing the differentiation of immune cells in specific tissue oxygenation profiles, allowing for better immune responses.
Understanding the interplay between physiological oxygenation and immune function opens new therapeutic avenues to enhance immune responses in health and disease. Explore the latest research on oxygen-sensing pathways for exciting developments in immunotherapy!
Mirchandani, A. S., Sanchez-Garcia, M. A., & Walmsley, S. R. (2024). How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia. Nature Reviews Immunology. https://doi.org/10.1038/s41577-024-01087-5
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