Lipopolysaccharide induces HIF-1α accumulation via MAPK p38-mediated mRNA stabilization and dexamethasone-sensitive protein stabilization.

In macrophages, the hypoxia-inducible transcription factor 1α (HIF-1α) can be activated under normoxic conditions by proinflammatory agonists such as lipopolysaccharide (LPS). This noncanonical HIF-1α activation allows macrophages to accommodate rapidly changing demands for energy and biosynthetic precursors in the face of an immune challenge. Alterations in HIF-1α hydroxylation and proteolysis have been implicated in the response, but the involvement of other signaling mechanisms and pathways is unclear. Here, we use genetic and pharmacological approaches to show that LPS-induced HIF-1α accumulation in primary macrophages is dependent on mitogen-activated protein kinase p38 and mediated by the phosphorylation and inactivation of tristetraprolin, an mRNA destabilizing protein that targets Hif1a mRNA for degradation. We previously reported that the glucocorticoid dexamethasone inhibits LPS-induced HIF-1α accumulation and metabolic reprogramming in primary macrophages. Here, we tested and disproved the hypothesis that dexamethasone exerts this effect via the mitogen-activated protein kinase p38 inactivator dual specificity phosphatase 1. Hence, two novel mechanisms critically regulate HIF-1α activation in LPS-treated macrophages: a p38-dependent mechanism that operates at the post-transcriptional level to control Hif1a mRNA stability, and a glucocorticoid-sensitive mechanism that operates at the post-translational level to control HIF-1α protein stability. Combined targeting of these two mechanisms may exert therapeutic effects in contexts where HIF-1α contributes to immune-mediated inflammatory pathology.