The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Constitutive Endocytosis of CD163 Mediates Hemoglobin-Heme Uptake and Determines the Noninflammatory and Protective Transcriptional Response of Macrophages to Hemoglobin
Abstract
Heme toxicity contributes to the pathogenesis of chronic inflammatory diseases, atherosclerosis, and hemolysis associated vasculopathy. Macrophage clearance of cell free hemoglobin (Hb) is thus an essential homeostatic function of these cells. We examined the transcriptional response of human PBMC derived macrophages to Hb by gene array analysis. The observed noninflammatory macrophage response was characterized by induction of an antioxidative and antiinflammatory gene expression pattern with most prominent induction of the inducible heme oxygenase (HO-1). The metabolically active Hb-CD163-HO-1 pathway resulted in synthesis of ferritin—1 of the antioxidative and antiinflammatory end products linked to heme breakdown by HO-1. This response was mediated by the Hb scavenger receptor CD163 and heme and was not related to Hb mediated depletion of reduced glutathione. In contrast to other cellular responses induced by CD163, there was no role of protein phosphorylation dependent CD163 signaling in the protective macrophage response to Hb. Instead, CD163 acted as an Hb transporter, which undergoes constitutive and ligand independent internalization and recycling between the cell surface and early endosomes. The expression of CD163 and HO-1 in macrophages of neovascularized atherosclerotic lesions suggests that the pathway described herein is active in vivo. Noninflammatory Hb clearance and intimately linked HO-1 expression may provide the long sought-after explanation for the antiinflammatory activity associated with CD163-positive macrophages.
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“Hemophagocytes are also a source of heme-oxygenase 1, another mediator of antiinflammatory responses (41).”
From Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice (2011) · cites this paper as [41]
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Cites
Signals for Sorting of Transmembrane Proteins to Endosomes and Lysosomes
Bonifacino, J. S., & Traub, L. M. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161800 · Cited by 2,040
Identification of the haemoglobin scavenger receptor
Kristiansen, M., Graversen, J. H., Jacobsen, C., Sonne, O., Hoffman, H.-J., Law, S. K. A., & Moestrup, S. K. (2001) · Nature · doi:10.1038/35051594 · Cited by 1,712
The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin
Rother, R. P., Bell, L. B., Hillmen, P., & Gladwin, M. T. (2005) · JAMA · doi:10.1001/jama.293.13.1653 · Cited by 1,565
Heme oxygenase-1: unleashing the protective properties of heme
Otterbein, L. E., Soares, M. P., Yamashita, K., & Bach, F. H. (2003) · Trends in Immunology · doi:10.1016/s1471-4906(03)00181-9 · Cited by 1,166
Heme oxygenase: colors of defense against cellular stress
Otterbein, L. E., & Choi, A. M. K. (2000) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2000.279.6.l1029 · Cited by 870
Pro-oxidant and cytotoxic effects of circulating heme
Jeney, V., Balla, J., Yachie, A., Varga, Z., Vercellotti, G. M., Eaton, J. W., & Balla, G. (2002) · Blood · doi:10.1182/blood.v100.3.879 · Cited by 633
Different Faces of the Heme-Heme Oxygenase System in Inflammation
Wagener, F. A. D. T. G., Volk, H., Willis, D., Abraham, N. G., Soares, M. P., Adema, G. J., & Figdor, C. G. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.3.5 · Cited by 537
Philippidis, P., Mason, J. C., Evans, B. J., Nadra, I., Taylor, K. M., Haskard, D. O., & Landis, R. C. (2004) · Circulation Research · doi:10.1161/01.res.0000109414.78907.f9 · Cited by 476
Sun, J., Brand, M., Zenke, Y., Tashiro, S., Groudine, M., & Igarashi, K. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308083100 · Cited by 364
Juan, S., Lee, T., Tseng, K., Liou, J., Shyue, S., Wu, K. K., & Chau, L. (2001) · Circulation · doi:10.1161/hc3801.095663 · Cited by 333
Oxygen therapeutics: can we tame haemoglobin?
Alayash, A. I. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1307 · Cited by 305
Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice
Ishikawa, K., Sugawara, D., Wang, X.-P., Suzuki, K., Itabe, H., Maruyama, Y., & Lusis, A. J. (2001) · Circulation Research · doi:10.1161/01.res.88.5.506 · Cited by 296
Schaer, D. J., Schaer, C. A., Buehler, P. W., Boykins, R. A., Schoedon, G., Alayash, A. I., & Schaffner, A. (2006) · Blood · doi:10.1182/blood-2005-03-1014 · Cited by 285
Self-citationAbsence of heme oxygenase‐1 exacerbates atherosclerotic lesion formation and vascular remodeling
Yet, S., Layne, M. D., Liu, X., Chen, Y., Ith, B., Sibinga, N. E. S., & Perrella, M. A. (2003) · The FASEB Journal · doi:10.1096/fj.03-0187fje · Cited by 283
HUMAN MONOCYTES EXPRESS CD163, WHICH IS UPREGULATED BY IL-10 AND IDENTICAL TO p155
Sulahian, T. H., Högger, P., Wahner, A. E., Wardwell, K., Goulding, N. J., Sorg, C., Droste, A., Stehling, M., Wallace, P. K., Morganelli, P. M., et al. (2000) · Cytokine · doi:10.1006/cyto.2000.0720 · Cited by 281
Endothelial Heme Oxygenase-1 Induction by Hypoxia
Motterlini, R., Foresti, R., Bassi, R., Calabrese, V., Clark, J., & Green, C. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.18.13613 · Cited by 261
Turkseven, S., Kruger, A., Mingone, C. J., Kaminski, P., Inaba, M., Rodella, L. F., Ikehara, S., Wolin, M. S., & Abraham, N. G. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00024.2005 · Cited by 256
Zwadlo, G., Voegeíi, R., Schulze‐Osthoff, K., & Sorg, C. (2008) · Experimental Cell Biology · doi:10.1159/000163432 · Cited by 243
Regulation of CD163 on human macrophages: cross-linking of CD163 induces signaling and activation
van den Heuvel, M. M., Tensen, C. P., van As, J., van den Berg, T. K., Fluitsma, D. M., Dijkstra, C. D., Döpp, E. A., Droste, A., van Gaalen, F. A., Sorg, C., et al. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.5.858 · Cited by 222
Berberat, P. O., Katori, M., Kaczmarek, E., Anselmo, D., Lassman, C., Ke, B., Shen, X., Busuttil, R. W., Yamashita, K., Csizmadia, E., et al. (2003) · The FASEB Journal · doi:10.1096/fj.03-0229fje · Cited by 207
Schaer, D. J., Schleiffenbaum, B. E., Kurrer, M. O., Imhof, A., Bächli, E., Fehr, J., Møller, H. J., Moestrup, S. K., & Schaffner, A. (2004) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2004.00318.x · Cited by 203
Self-citationHarris, S. G., & Phipps, R. P. (2001) · European Journal of Immunology · doi:10.1002/1521-4141(200104)31:4 · Cited by 195
Glutathione Depletion Induces Heme Oxygenase‐1 (HSP32) mRNA and Protein in Rat Brain
Ewing, J. F., & Maines, M. D. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03315.x · Cited by 178
Sardana, M. K., & Kappas, A. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.8.2464 · Cited by 168
Rapid endocytosis of the transferrin receptor in the absence of bound transferrin.
Watts, C. K. W. (1985) · The Journal of Cell Biology · doi:10.1083/jcb.100.2.633 · Cited by 167
Kruger, A. L., Peterson, S. J., Türkseven, S., Kaminski, P. M., Zhang, F. F., Quan, S., Wolin, M. S., & Abraham, N. G. (2005) · Circulation · doi:10.1161/circulationaha.104.517102 · Cited by 165
Tulis, D. A., Durante, W., Liu, X., Evans, A. J., Peyton, K. J., & Schafer, A. I. (2001) · Circulation · doi:10.1161/hc4701.099585 · Cited by 162
Schaer, D. J., Boretti, F. S., Schoedon, G., & Schaffner, A. (2002) · British Journal of Haematology · doi:10.1046/j.1365-2141.2002.03790.x · Cited by 135
Self-citationHeme Oxygenase-1 Inhibits Atherogenesis in Watanabe Heritable Hyperlipidemic Rabbits
Ishikawa, K., Sugawara, D., Goto, J., Watanabe, Y., Kawamura, K., Shiomi, M., Itabe, H., & Maruyama, Y. (2001) · Circulation · doi:10.1161/hc3901.095897 · Cited by 130
Overexpression of Glutamate-Cysteine Ligase Extends Life Span in Drosophila melanogaster
Orr, W. C., Radyuk, S. N., Prabhudesai, L., Toroser, D., Benes, J. J., Luchak, J. M., Mockett, R. J., Rebrin, I., Hubbard, J. G., & Sohal, R. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508272200 · Cited by 124
Oxidative-stress response in vascular endothelial cells exposed to acellular hemoglobin solutions
Motterlini, R., Foresti, R., Vandegriff, K. D., Intaglietta, M., & Winslow, R. M. (1995) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1995.269.2.h648 · Cited by 121
Induction of Heme Oxygenase 1 by Nitrosative Stress
NAUGHTON, P. J., Foresti, R., Bains, S. K., Hoque, M., Green, C. J., & Motterlini, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203863200 · Cited by 112
Schaer, D. J., Boretti, F. S., Hongegger, A., Poehler, D., Linscheid, P., Staege, H., Mueller, C., Schoedon, G., & Schaffner, A. (2001) · Immunogenetics · doi:10.1007/s002510100304 · Cited by 80
Self-citationThe macrophage scavenger receptor CD163: endocytic properties of cytoplasmic tail variants
Nielsen, M. J., Madsen, M. M., Møller, H. J., & Moestrup, S. K. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.1005602 · Cited by 63
Schaer, D. J. (2002) · Atherosclerosis · doi:10.1016/s0021-9150(01)00756-0 · Cited by 29
Self-citationD’Agnillo, F., & Alayash, A. I. (2000) · Journal of neurosurgery · doi:10.3171/jns.2000.92.5.0899 · Cited by 7
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Crayne, C. B., Albeituni, S., Nichols, K. E., & Cron, R. Q. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00119 · Cited by 633
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Ceciliani, F., Cerón, J. M. C., Eckersall, P. D., & Sauerwein, H. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.04.004 · Cited by 579
Gene-edited pigs are protected from porcine reproductive and respiratory syndrome virus
Whitworth, K. M., Rowland, R. R. R., Ewen, C., Trible, B. R., Kerrigan, M. A., Cino-Ozuna, A. G., Samuel, M., Lightner, J. E., McLaren, D. G., Mileham, A. J., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3434 · Cited by 565
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Kernan, K. F., & Carcillo, J. A. (2017) · International Immunology · doi:10.1093/intimm/dxx031 · Cited by 638
Metadata
- Authors
- Schaer, C. A., Schoedon, G., Imhof, A., Kurrer, M. O., & Schaer, D. J.
- Affiliations
- University Hospital Zurich (CH)
- Venue
- Circulation Research
- Published
- 2006-10-27
- Volume
- 99
- Issue
- 9
- Pages
- 943-950
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2114374333
- Cited by
- 267
- References
- 36
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 12 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 11 · 2019: 11 · 2018: 13 · 2017: 19 · 2016: 19 · 2015: 19 · 2014: 19 · 2013: 16 · 2012: 16
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- CD163, free hemoglobin, heme toxicity, heme oxygenase-1, endocytosis, atherosclerosis, neovascularization, oxidative stress, endosomal recycling
- MeSH terms
- CD163 Antigen, Cells, Cultured, Endocytosis, Glutathione, Heme, Hemoglobins, Humans, Inflammation, Macrophages, Neovascularization, Pathologic, Receptors, Cell Surface, Endosomes, RNA, Messenger, Transcription, Genetic, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Gene Expression Regulation, Enzymologic, Cytoprotection, Gene Expression Profiling, Atherosclerosis, Receptors, Scavenger, Heme Oxygenase-1
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