Abstract
Dendritic cells(DCs) are important sentinels of the immune system and frequently reside in areas of low oxygen availability, in particular in the course of inflammatory processes. Hypoxia-inducible transcription factor (HIF)1α is responsible for major alterations in gene expression as part of the cellular adaptation to low oxygen concentration. In this study, we generated mice with a conditional deletion of HIF1α in DCs. Bone marrow-derived DCs from WT and conditional mutant mice expressed elevated levels of major histocompatibility complex class II and CD86 when grown in a hypoxic environment, whereas production of the cytokines interleukin (IL)-12p70, IL-10, IL-6, TNF-α, IL-1β, and IL-23 was reduced, both independent of HIF1α expression. In contrast, secretion of IL-22 was strongly enhanced under hypoxic conditions in an HIF1α-dependent manner. The chemokine receptor CCR7 was expressed at higher levels in wild-type DCs compared with HIF1α-deficient DCs, whereas the production of CCL17 and CCL22 was increased in conditions of low oxygen. Using in vitro as well as in vivo migration assays, we observed an enhanced migratory capability of DCs generated under hypoxia, which was HIF1α-dependent. Taken together, our data indicate that HIF1α plays an important role for DC differentiation and migration in a low oxygen environment.
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