Role of the Hypoxia-Inducible Factor-1alpha and Akt on hypoxia-induced migratory program in dendritic cells

Dendritic cells (DCs) are the most potent antigen-presenting cells and, during their life cycle, are exposed to different oxygen tensions. One of the essential functions of DCs is to migrate from/into sites characterized by a low oxygen environment. Therefore, their migratory properties may be affected by such environment with important consequences in immune response regulation, inflammation and tumour microenvironment. In the present study, we show that short-term hypoxia positively activates a migratory program in human monocyte-derived DCs regardless of the applied chemotactic stimuli. To directly study the role of HIF-1alpha, the master regulator of hypoxia-induced adaptative responses, we inhibited HIF-1alpha expression by RNA interference in DCs and thereafter a chemotactic assay was performed. Of interest, hypoxia did not enhance cell migration in immature DC silenced for HIF-1alpha, when compared with the normoxic control. In contrast, chemotaxis was still increased in mature DCs silenced for HIF-1alpha exposed to hypoxia versus normoxia. In an attempt to explain this unexpected results we evaluated several pathways involved in cell migration and we observed that hypoxia significantly enhances the phosphorylation of Akt, a protein which is associated with DC migration and maturation. Indeed, hypoxia-induced cell migration was abolished by specific Akt pathway inhibitors, also in mature DCs silenced for HIF-1alpha, indicating that Akt could be an alternative pathway to be activated in hypoxic DCs. Our results may contribute to further understand the modality by which hypoxia may affect DC migration with important implications in the regulation of the immune response.