The role of redox‐dependent mechanisms in the downregulation of ligand‐induced Toll‐like receptors 7, 8 and 4‐mediated HIF‐1α prolyl hydroxylation

Toll-like receptors (TLRs) are key components of the innate immune system that allow immune cells to specifically detect pathogens by recognizing their specific molecular patterns. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is known to have a critical role in TLR downstream signalling by promoting energy metabolism, expression of proinflammatory cytokines and proangiogenic factors. However, the molecular mechanisms leading to the accumulation of HIF-1 alpha are not fully understood. In this study, we report that R848 (specific ligand)-induced activation of endosomal TLRs 7 and 8 (which recognize viral single-stranded RNA) and lipopolysaccharide (LPS)-induced activation of TLR4 (which specifically recognizes LPS as a ligand) leads to downregulation of degradative HIF-1 alpha prolyl hydroxylation. In the case of TLR7/8, this downregulation is achieved through redox- and reactive nitrogen species (RNS)-dependent mechanisms. S-nitrosation of HIF-1 alpha protein was also observed. In the case of LPS-induced TLR4 activation, only a redox-dependent mechanism is involved. RNS and p38 MAP kinase (known to contribute to LPS-induced TLR4-dependent accumulation of HIF-1 alpha protein) do not affect HIF-1 alpha prolyl hydroxylation. In both cases, downregulation of HIF-1 alpha prolyl hydroxylation correlates with a decrease in intracellular iron (II).