HIF‐1α inhibition in macrophages preserves acute liver failure by reducing IL‐1β production

Abstract

The development of acute liver failure (ALF) is dependent on its local inducer. Inflammation is a high‐frequency and critical factor that accelerates hepatocyte death and liver failure. In response to injury stress, the expression of the transcription factor hypoxia‐inducible factor‐1α (HIF‐1α) in macrophages is promoted by both oxygen‐dependent and oxygen‐independent mechanisms, thus promoting the expression and secretion of the cytokine interleukin‐1β (IL‐1β). IL‐1β further induces hepatocyte apoptosis or necrosis by signaling through the receptor (IL‐1R) on hepatocyte. HIF‐1α knockout in macrophages or IL‐1R knockout in hepatocytes protects against liver failure. However, whether HIF‐1α inhibition in macrophages has a protective role in ALF is unclear. In this study, we revealed that the small molecule HIF‐1α inhibitor PX‐478 inhibits the expression and secretion of IL‐1β, but not tumor necrosis factor α (TNFα), in bone marrow‐derived macrophages (BMDMs). PX‐478 pretreatment alleviates liver injury in LPS/D‐GalN‐induced ALF mice by decreasing the hepatic inflammatory response. In addition, preventive or therapeutic administration of PX‐478 combined with TNFα neutralizing antibody markedly improved LPS/D‐GalN‐induced ALF. Taken together, our data suggest that PX‐478 administration leads to HIF‐1α inhibition and decreased IL‐1β secretion in macrophages, which represents a promising therapeutic strategy for inflammation‐induced ALF.