Macrophage metabolic adaptation to heme detoxification involves CO-dependent activation of the pentose phosphate pathway.

Heme is an essential cofactor for numerous cellular functions, but release of free heme during hemolysis results in oxidative tissue damage, vascular dysfunction, and inflammation. Macrophages play a key protective role in heme clearance; however, the mechanisms that regulate metabolic adaptations that are required for effective heme degradation remain unclear. Here we demonstrate that heme loading drives a unique bioenergetic switch in macrophages, which involves a metabolic shift from oxidative phosphorylation toward glucose consumption. Metabolomic and transcriptional analysis of heme-loaded macrophages revealed that glucose is funneled into the pentose phosphate pathway (PPP), which is indispensable for efficient heme detoxification and is required to maintain redox homeostasis. We demonstrate that the metabolic shift to the PPP is controlled by heme oxygenase-dependent generation of carbon monoxide (CO). Finally, we show that PPP upregulation occurs in vivo in organ systems central to heme clearance and that PPP activity correlates with heme levels in mouse sickle cell disease (SCD). Together, our findings demonstrate that metabolic adaptation to heme detoxification in macrophages requires a shift to the PPP that is induced by heme-derived CO, suggesting pharmacologic targeting of macrophage metabolism as a novel therapeutic strategy to improve heme clearance in patients with hemolytic disorders.

Macrophage metabolism in atherosclerosis.

A key aspect of atherosclerosis is the maladaptive inflammatory response to lipoprotein accumulation in the artery. The failure to decrease lipid accumulation, to clear apoptotic cells, and to resolve inflammation ultimately leads to macrophage accumulation within the vascular wall [Thorp EB (2010) Apoptosis15, 1124-1136; Moore K et al. (2013) Nat Rev Immunol 13, 709-721; Moore KJ and Tabas I (2011) Cell 145, 341-355; Ley K et al. (2011) Arterioscler Thromb Vasc Biol 31, 1506-1516]. Several subsets of macrophages are found inside atherosclerotic plaques [Chinetti-Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10-17; Leitinger N and Schulman IG (2013) Arterioscler Thromb Vasc Biol 33, 1120-1126; Mantovani A et al. (2009) Arterioscler Thromb Vasc Biol 29, 1419-1423]: Proinflammatory M1-like macrophages potentially participate in atherosclerosis initiation and progression; M2-like macrophages are thought to be protective due to their anti-inflammatory and profibrotic properties, presumably stabilizing the plaque [Chistiakov DA et al. (2015) Int J Cardiol 184, 436-445; Gordon S (2003) Nat Rev Immunol 3, 23-35]; Mox macrophages develop in response to oxidized phospholipids and present a glutathione- and potentially redox-regulating phenotype [Kadl A et al. (2010) Circ Res 107, 737-746]; Mhem macrophages are found in areas of plaque hemorrhage [Boyle JJ et al. (2009) Am J Pathol 174, 1097-1108; Boyle JJ et al. (2012) Circ Res 110, 20-33] where they are involved in heme clearance. Recent evidence suggests that the relative abundance of these macrophage subsets is a better indicator of plaque progression and stability than the total number of lesion macrophages [Chinetti-Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10-17]. Over the last few years, findings in the area of immunometabolism established a link between the metabolic state of the different macrophage phenotypes and their functions [O'Neill LAJ and Pearce EJ (2016) J Exp Med 213, 15-23]. However, the effect of metabolic changes in macrophages on atherosclerotic plaque progression and stability is not well understood and an area of intensive study. In this review, we will summarize and critically discuss recent developments in the field of macrophage metabolism in the context of atherosclerosis to guide future investigation in this area.