Fig. 7.
The role for HIF1α in M1 macrophage metabolic phenotype. HIF1α is activated and stabilized under two oxidatively regulated pathways after inflammatory receptor engagement by H2O2 that is generated from NOX2. One the one hand, activated AKT indirectly activates the mTOR complex and HIF1α is upregulated. Further activation of HIF1α is achieved by nitrosylation of its oxygen dependent domain (ODD). Consequently, the VHL protein cannot bind to HIF1α and the protein is not directed towards degradation by the proteasome. With increased stability comes increased transcriptional activity and HIF1α promotes increased expression of inflammatory (IL1α) and metabolic (hexokinase HK, phosphofructokinase PFK, nicotinamide phosphoribosyltransferase NAMPT and glucose transporter 1 GLUT1) genes. The net consequence is that glycolysis activity is increased in M1 macrophages.