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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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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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