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‐1α (HIF‐1α) 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‐1α 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‐1α 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‐1α 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‐1α protein) do not affect HIF‐1α prolyl hydroxylation. In both cases, downregulation of HIF‐1α prolyl hydroxylation correlates with a decrease in intracellular iron (II).