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; Dominik J Schaer

doi:10.1189/jlb.0407226

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

J Leukoc Biol. 2008 Feb;83(2):325-33. doi: 10.1189/jlb.0407226. Epub 2007 Oct 18.

Authors

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

Affiliation

¹ Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland.

PMID: 17947394
DOI: 10.1189/jlb.0407226

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, CD / genetics
Antigens, CD / isolation & purification
Antigens, CD / metabolism*
Antigens, Differentiation, Myelomonocytic / genetics
Antigens, Differentiation, Myelomonocytic / isolation & purification
Antigens, Differentiation, Myelomonocytic / metabolism*
Cation Transport Proteins / metabolism
Cell Line
Dexamethasone / pharmacology
Endocytosis
Endosomes / metabolism
Gene Expression Regulation / drug effects
Haptoglobins / metabolism*
Heme / metabolism
Hemoglobins / metabolism*
Humans
Interferon-gamma / pharmacology
Iron / metabolism
Kidney
Macrophage Activation* / drug effects
Macrophages / drug effects
Macrophages / metabolism*
Membrane Transport Proteins / biosynthesis
Membrane Transport Proteins / genetics
Membrane Transport Proteins / isolation & purification
Membrane Transport Proteins / metabolism*
Models, Biological
Protein Interaction Mapping
Proton-Coupled Folate Transporter
RNA, Messenger / biosynthesis
Receptors, Cell Surface / genetics
Receptors, Cell Surface / isolation & purification
Receptors, Cell Surface / metabolism*
Recombinant Fusion Proteins / metabolism
Toll-Like Receptors / agonists

Substances

Antigens, CD
Antigens, Differentiation, Myelomonocytic
CD163 antigen
Cation Transport Proteins
Haptoglobins
Hemoglobins
Membrane Transport Proteins
Proton-Coupled Folate Transporter
RNA, Messenger
Receptors, Cell Surface
Recombinant Fusion Proteins
SLC46A1 protein, human
Toll-Like Receptors
haptoglobin-hemoglobin complex
hemoglobin-haptoglobin receptor
metal transporting protein 1
Heme
Dexamethasone
Interferon-gamma
Iron