Abstract
Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.
Highlights
Immune cells and proper immune response require focal sites of immune cell development, maturation, activation, tolerance, and longevity defined as immunological niches bearing a certain microenvironment to maintain immune homeostasis [1]
The major organs of the immune system, including bone marrow [23,24], thymus [24,25,26], spleen [26,27], and lymph nodes [28], exhibit regions of immune activity with locally significantly lower pO2 than surrounding tissues and even lower than inhaled air. These hypoxic regions are of functional importance because they impact immunity by providing a niche for hematopoietic stem cells (HSCs) in the bone marrow, where hypoxia maintains the self-renewal capacity of HSCs favors a slow turnover of HSCs and sustains survival by promoting their quiescence [29,30,31,32] or an environment for the antigen challenging of B cells in germinal centers (GCs), where hypoxia increase glycolytic metabolism supporting the generation and expansion of antigen-specific GC B cells and the production of high-affinity immunoglobulin G (IgG) antibodies [33,34]
Apart from the O2 -independent posttranslational and translation regulation of hypoxiainducible factors (HIFs)’s, HIF-α can be induced by a variety of inflammatory stimuli such as bacterial products, tumor necrosis factor-α (TNF-α) and IL-1β which can lead to the activation of pathways successively engaging phosphatidylinositol 3-kinase (PI3K), Protein kinase B
Summary
Immune cells and proper immune response require focal sites of immune cell development, maturation, activation, tolerance, and longevity defined as immunological niches bearing a certain microenvironment to maintain immune homeostasis [1]. These organs and tissues include the bone marrow, placenta, intestinal mucosa, renal medulla, secondary lymphoid organs, and the thymus [2,3]. Hypoxia arises in aIfvariconstant supply with oxygen does not anymore meet the requirements of cells, hypoxic ety of immunological situations under physiological and pathophysiological immune acconditions will be established and, if sustained, these conditions will result in tivity [10,11]. Hypoxia arises in a variety of immunological situations under physiological and pathophysiological immune activity [10,11]
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