The haptoglobin-CD163-heme oxygenase-1 pathway for hemoglobin scavenging

Jens Haugbølle Thomsen, Anders Etzerodt, Pia Svendsen, Søren K Moestrup, Jens Haugbølle Thomsen, Anders Etzerodt, Pia Svendsen, Søren K Moestrup

Abstract

The haptoglobin- (Hp-) CD163-heme oxygenase-1 (HO-1) pathway is an efficient captor-receptor-enzyme system to circumvent the hemoglobin (Hb)/heme-induced toxicity during physiological and pathological hemolyses. In this pathway, Hb tightly binds to Hp leading to CD163-mediated uptake of the complex in macrophages followed by lysosomal Hp-Hb breakdown and HO-1-catalyzed conversion of heme into the metabolites carbon monoxide (CO), biliverdin, and iron. The plasma concentration of Hp is a limiting factor as evident during accelerated hemolysis, where the Hp depletion may cause serious Hb-induced toxicity and put pressure on backup protecting systems such as the hemopexin-CD91-HO pathway. The Hp-CD163-HO-1 pathway proteins are regulated by the acute phase mediator interleukin-6 (IL-6), but other regulatory factors indicate that this upregulation is a counteracting anti-inflammatory response during inflammation. The heme metabolites including bilirubin converted from biliverdin have overall an anti-inflammatory effect and thus reinforce the anti-inflammatory efficacy of the Hp-CD163-HO-1 pathway. Future studies of animal models of inflammation should further define the importance of the pathway in the anti-inflammatory response.

Figures

Figure 1
Figure 1
The CD163 pathway for uptake of Hb-Hp complexes and the CD91 pathway for uptake of hemopexin- (Hx-) heme complexes. The endocytosis of the ligand leads to degradation in lysosomes while the receptor recycles from the endosomes back to the plasma membrane.
Figure 2
Figure 2
The intracellular pathway for heme-degradation subsequent to CD163 and CD91 mediated endocytosis in macrophages. Free heme is degraded to biliverdin, CO, and ferrous iron by the endoplasmic reticulum enzyme HO-1 facing the cytosol. Electrons are delivered by NADPH p450 cytochrome reductase. Biliverdin is reduced to bilirubin by biliverdin reductase and transported to the liver bound to albumin.

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