title: Heme carrier protein (HCP-1) spatially interacts with the CD163 hemoglobin uptake pathway and is a target of inflammatory macrophage activation.
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.
authors.affiliation: Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Schaer
authors.forename: Florence
authors.initials: F
authors.lastname: Vallelian
authors.forename: Alexander
authors.initials: A
authors.lastname: Imhof
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoedon
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Schaer
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006242:Haptoglobins / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007668:Kidney; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D008954:Models, Biological; D025941:Protein Interaction Mapping; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists; D000098902:CD163 Antigen; D000098742:Ferroportin
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D027682:Cation Transport Proteins; D006242:Haptoglobins; D006454:Hemoglobins; D026901:Membrane Transport Proteins; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C505058:SLC46A1 protein, human; D051193:Toll-Like Receptors; C035492:haptoglobin-hemoglobin complex; C027079:hemoglobin-haptoglobin receptor; D000098742:Ferroportin; D006418:Heme; D003907:Dexamethasone; D007371:Interferon-gamma; D007501:Iron