Abstract
Hypoxia is an inherent factor in the inflammatory process and is important in the regulation of some immune cell functions, including the expression of mast cell pro- and anti-inflammatory mediators. Hypoxia also influences cell adhesion to the extracellular matrix (ECM). Hyaluronic acid is one of the major components of the ECM that is involved in inflammatory and tissue regeneration processes in which mast cells play a prominent role. This prompted us to investigate the effects of hypoxia on the expression of hyaluronic acid receptors in mast cells and mast cell adhesion to this ECM component. We found that human LAD2 mast cells spontaneously adhered to hyaluronic acid in a CD44-dependent manner and that reduced oxygen concentrations inhibited or even completely abolished this adhesion process. The mechanism of hypoxia downregulation of mast cell adhesion to hyaluronic acid did not involve a decrease in CD44 expression and hyaluronidase-mediated degradation of adhesion substrates but rather conformational changes in the avidity of CD44 to hyaluronic acid. Hypoxia-mediated regulation of mast cell adhesion to extracellular matrix components might be involved in the pathogenic accumulation of mast cells observed in the course of certain diseases including rheumatoid arthritis and cancer.
Highlights
Oxygen is an element that is necessary for the proper function of cells in living organisms
Investigated genes included the major hyaluronic acid (HA) receptor CD44, genes coding for alternative HA receptors, such as hyaluronan-mediated motility (HMMR/RHAMM), intercellular adhesion molecule 1 (ICAM-1), lymphatic vessel endothelial receptor 1 (LYVE-1) [27, 28], TLR2 and TLR4, which were reported to interact with low molecular weight HA [27], and five genes encoding HYAL1-5 hyaluronidases [29]
The effect of hypoxia on cell adhesion has been reported for other cell types and seems to be cell type- and adhesion substrate-specific, as hypoxia increases the adhesion of lymphocytes to mesenchymal cells [35] and neutrophils to the endothelium [36, 37] and inhibits the adhesion of several tumor cell lines to fibronectin, collagen type I, and vitronectin [38]
Summary
Oxygen is an element that is necessary for the proper function of cells in living organisms. The oxygen concentration in various tissues is significantly lower than that in atmospheric conditions; e.g., in venous blood, it is approximately 5.3%, while in the superficial region of the skin, it is only 1.1%. Certain pathological processes result in local hypoxia. The tumor formation process, which can be considered a special type of inflammation, is associated with local hypoxia [3, 4]. In vitro cell culture incubators use an oxygen concentration corresponding to that in the air, which is frequently referred to as “normoxia.” Since cell lines have been derived and cultured under such conditions, lowering the oxygen concentration to physioxic levels may be treated by these cells as hypoxia and is frequently applied as an in vitro model of hypoxia [1]. Oxygen-sensing prolyl hydroxylases (PHDs) and hypoxia-inducible factors (HIFs), such as HIF-1α and HIF-2α, are critical for initiating the cellular response to hypoxia, which includes changes in cell metabolism as well as other cellular functions, including remodeling of the extracellular matrix (ECM), cell adhesion, and migration [5,6,7,8]
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