title: Identification of the receptor scavenging hemopexin-heme complexes.
abstract: Heme released from heme-binding proteins on internal hemorrhage, hemolysis, myolysis, or other cell damage is highly toxic due to oxidative and proinflammatory effects. Complex formation with hemopexin, the high-affinity heme-binding protein in plasma and cerebrospinal fluid, dampens these effects and is suggested to facilitate cellular heme metabolism. Using a ligand-affinity approach, we purified the human hemopexin-heme receptor and identified it as the low-density lipoprotein receptor-related protein (LRP)/CD91, a receptor expressed in several cell types including macrophages, hepatocytes, neurons, and syncytiotrophoblasts. Binding experiments, including Biacore analysis, showed that hemopexin-heme complex formation elicits the high receptor affinity. Uptake studies of radio-labeled hemopexin-heme complex in LRP/CD91-expressing COS cells and confocal microscopy of the cellular processing of fluorescent hemopexin-heme complex established the ability of LRP/CD91 to mediate hemopexin-heme internalization resulting in cellular heme uptake and lysosomal hemopexin degradation. Uptake of hemopexin-heme complex induced LRP/CD91-dependent heme-oxygenase 1 mRNA transcription in cultured monocytes. In conclusion, hemopexin-heme complexes are removed by a receptor-mediated pathway showing striking similarities to the CD163-mediated haptoglobin-hemoglobin clearance in macrophages. Furthermore, the data indicate a hitherto unknown role of LRP/CD91 in inflammation.
authors.affiliation: Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Hvidberg
authors.forename: Maciej B
authors.initials: MB
authors.lastname: Maniecki
authors.forename: Christian
authors.initials: C
authors.lastname: Jacobsen
authors.forename: Peter
authors.initials: P
authors.lastname: Højrup
authors.forename: Holger J
authors.initials: HJ
authors.lastname: Møller
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D019556:COS Cells; D002522:Chlorocebus aethiops; D004591:Electrophoresis, Polyacrylamide Gel; D004705:Endocytosis; D006418:Heme / Q000737:chemistry*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006466:Hemopexin / Q000737:chemistry*; D006470:Hemorrhage / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008264:Macrophages / Q000378:metabolism; D018613:Microscopy, Confocal; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D013997:Time Factors; D000511:alpha-Macroglobulins / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D006454:Hemoglobins; C475476:LRP1 protein, human; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D000511:alpha-Macroglobulins; D006418:Heme; D006466:Hemopexin; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D010100:Oxygen