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Originally published online as doi:10.1189/jlb.0407226 on October 18, 2007

Published online before print October 18, 2007
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(Journal of Leukocyte Biology. 2008;83:325-333.)
© 2008 by Society for Leukocyte Biology

Heme carrier protein (HCP-1) spatially interacts with the CD163 hemoglobin uptake pathway and is a target of inflammatory macrophage activation

Christian A. Schaer, Florence Vallelian, Alexander Imhof, Gabriele Schoedon and Dominik J. Schaer1

Department of Medicine, University Hospital, Zurich, Switzerland

1 Correspondence: Medical Clinic Research Unit, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: dominik.schaer{at}usz.ch

Macrophages constitute the major cellular compartment for hemoglobin (Hb) degradation and subsequent recycling of heme-iron to erythropoiesis. Dysregulation of macrophage iron and heme metabolism is a major pathophysiologic determinant of anemia of chronic disease. In this study, we show that the heme transporter heme carrier protein 1 (HCP-1) is expressed in human macrophages. Within early endosomes, HCP-1 colocalizes with endocytosed Hb-haptoglobin (Hp) complexes, which are taken up via the CD163 scavenger receptor pathway. Hb-Hp passes the divalent metal transporter 1B/HCP-1-positive endosomal compartment on its route from the cell surface to lysosomes. HCP-1 mRNA and protein expression are down-regulated by stimulation of macrophages with various TLR agonists and IFN-{gamma}. The profound suppression of HCP-1 expression by inflammatory macrophage activation parallels the regulation of the iron exporter ferroportin. In contrast, dexamethasone enhanced HCP-1 expression significantly. Given the spatial relationship, we propose that the Hb scavenger receptor CD163 and HCP-1 constitute a linked pathway for Hb catabolism and heme-iron recycling in human macrophages.

Key Words: iron metabolism • inflammation • anemia of chronic disease




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