Abstract
Free heme is a very deleterious compound that promotes oxidation, inflammation and cell death, which contributes to numerous vascular pathologies including stroke, thrombosis and atherosclerosis. Rupture of red blood cells (RBC), also known as hemolysis, leads to the release of hemoglobin, which upon oxidation, readily releases free heme into the circulation. Due to their ability to clear heme and fight against heme-induced oxidative damage, macrophages limit tissue damage induced by hemolysis. Inside macrophages, heme is degraded by the inducible heme oxygenase 1 (Hmox-1), producing carbon monoxide (CO), iron and biliverdin. Macrophages respond to changes in their environment; they require a constant metabolic adaptation to sustain the bio-energetic demand. The pentose phosphate pathway (PPP) is the major source of NADPH, which is generated by glucose-6-phosphate dehydrogenase (G6PD) and phospho-gluconate dehydrogenase (PGD). NADPH provides reducing equivalents for numerous, Nrf2 (nuclear factor erythroid 2)-dependent anti-oxidant systems such as glutathione reductase and Hmox-1 itself. Here we show that intracellular free heme induces a specific metabolism in macrophages, characterized by increased glucose uptake, with no change in glycolysis, but a polarization towards the PPP. Pharmacologic inhibition of the PPP demonstrated that this metabolic shift is essential for macrophages to degrade heme efficiently. We also show that the metabolic adaptation to heme is dependent on Hmox activity, involving the upregulation of the glucose transporter (GLUT) 1, G6PD, and PGD. This suggests that CO is involved in the macrophage metabolic adaptation to heme. Finally we show that the PPP is increased in the liver of sickle-cell disease (SCD) mice, an accepted model of chronic intra-vascular hemolysis. This study provides a new understanding of macrophage metabolic adaptation to efficient heme clearance, opening the field for novel therapies for hemolysis-associated diseases.
Published Version
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