Oxygen sensing in myeloid cells : implications for physiology and cancer

Abstract

All mammals depend on oxygen in order to produce life-essential energy. They acquire oxygen (O₂) through inspiration. In the lungs, O₂ is gathered by erythrocytes that consequently deliver it to all cells by the cardiovascular system. O₂ levels vary within our bodies. The highest levels are measured in the respiratory system and at lowest in the most peripheral parts of the body, for example skin. Therefore, the physiological levels of O₂ are different in different tissues. During pathological events that result in challenged acquisition of O₂, such as disturbances in the bloodstream or sudden increases of the cell numbers, the need of O₂ often becomes higher than the demand; a condition defined as hypoxia. Because of this, mammals have developed responses that help to manage hypoxia at different levels.

Systemically, low O₂ levels are sensed by chemoreceptors that activate a chain of reflexes leading to more efficient O₂ delivery. Mammalian cells react to hypoxia by increasing O₂ independent energy production, which is done through glycolysis. Cells also activate signaling cascades that stimulate more efficient O₂ delivery in their environment. Cellular reactions to low O₂ are managed by hypoxia inducible factors (HIF), proteins that drive the expression of large amounts of genes necessary for survival in hypoxic environments. O₂ sensing is important for all mammalian cell types, however it is particularly crucial for motile cells that move through different tissues with a variable O₂ availability. Cells of the immune system need to function also in hypoxic environments. Mononuclear phagocytes (MP) are a group of multifunctional cells of the immune system that are highly dependent on HIF signaling and are also involved in numerous pathological conditions. Previous studies have shown that removal of HIF genes in MP results in dampened disease progression caused by environmental hypoxia, cancer or sepsis. Although the importance of HIF signaling in MP has been shown in several studies, very few of the studies describe the consequences of exaggerated HIF signaling in different states of diseases.

The work in this thesis aims to understand the role of myeloid hypoxia in pulmonary edema, cancer and sepsis, that has been described in three different studies attached to this thesis book. We have shown that augmented hypoxic response in MPs is enough to induce high-altitude pulmonary edema (HAPE)-like symptoms to such extent that it could be used as a model for studying pathological effects of environmental hypoxia in mice. In cancer, on the other hand, we showed that MP hypoxic response contributes to immune suppression by blocking cytotoxic lymphocyte proliferation. The MP-driven inhibition of lymphocyte proliferation occurred during antigen presentation, a process important for lymphocyte activation. Finally, in endotoxin induced sepsis, our studies demonstrated that removal of HIF-1α leads to decreased hypoglycemia due to reduced glycolysis. The strongest reduction in glycolysis was observed in the heart and brown fat. In conclusion, HIF signaling in MP plays a complex, yet important role in pathogenesis of several major diseases.