Hypoxia-mediated fine-tuning of the TLR7/9-triggered human PDC-derived IFN-α response is mediated by combined cellular and soluble IFN-regulators

Hypoxia occurs in settings where stringent control of inflammation is mandatory to avoid tissue damage. Here, we analyzed how hypoxia-induced mediators alter recognition of pathogen-derived molecular patterns (PAMPs). The most relevant finding was that hypoxia selectively targets IFN-α induced upon stimulation with nucleic acid-sensing Toll-like receptors (TLR7/8 and -9) in PBMC. Notably, IFN-α secretion was reduced, but IFN-α producing capacity preserved. Corroborating these findings IFN-dependent cytokines IP-10 and IL-12 p70 were reduced under hypoxia, while other cytokines such as TNF remained unaffected. A role for hypoxia-inducible factors (HIF) was confirmed with prolyl hydroxylase (PHD) inhibitors CoCl ₂ and DMOG. Plasmacytoid dendritic cells (PDC) were identified as the major source of IFN-α and experiments in B cell/PDC and monocyte/PDC cocultures indicated that T cells are not required and both lymphoid and myeloid cells equally support inhibition of IFN-α. Moreover, supernatants from unstimulated PBMC generated under hypoxic conditions were not suppressive but further experiments indicated that hypoxia-specific release of IFN-α regulators lactate and TGF-β can contribute to the IFN-α blockage and might synergize with PGE ₂ . However, each one of these factors alone is insufficient to block IFN-α secretion. These findings suggest that control of the PDC response occurs via combined soluble factors and cell contact-dependent mechanisms, thereby enabling a fine-tuning of the anti-microbial immune response in hypoxia.