CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms

Lysis of RBCs during numerous clinical settings such as severe hemolytic anemia, infection, tissue injury, or blood transfusion releases the endogenous damage-associated molecular pattern, hemoglobin (Hb), into the plasma. The redox-reactive Hb generates cytotoxic reactive oxygen species, disrupting...

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Main Authors: Subramanian, Karthik, Du, Ruijuan, Tan, Nguan Soon, Ho, Bow, Ding, Jeak Ling
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2014
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Online Access:https://hdl.handle.net/10356/101704
http://hdl.handle.net/10220/19771
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1017042020-03-07T12:24:53Z CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms Subramanian, Karthik Du, Ruijuan Tan, Nguan Soon Ho, Bow Ding, Jeak Ling School of Biological Sciences DRNTU::Science::Biological sciences Lysis of RBCs during numerous clinical settings such as severe hemolytic anemia, infection, tissue injury, or blood transfusion releases the endogenous damage-associated molecular pattern, hemoglobin (Hb), into the plasma. The redox-reactive Hb generates cytotoxic reactive oxygen species, disrupting the redox balance and impairing the immune-responsive blood cells. Therefore, it is crucial to understand how the immune system defends against the cytotoxic Hb. We identified a shortcut “capture and quench” mechanism of detoxification of Hb by the monocyte scavenger receptor CD163, independent of the well-known dominant antioxidant, haptoglobin. Our findings support a highly efficient two-pass mechanism of detoxification and clearance of Hb: 1) a direct suppression of Hb-pseudoperoxidase activity by CD163, involving an autocrine loop of CD163 shedding, sequestration of Hb, recycling, and homeostasis of CD163 in human monocytes and 2) paracrine transactivation of endothelial cells by the shedded soluble CD163 (sCD163), which further detoxifies and clears residual Hb. We showed that sCD163 and IgG interact with free Hb in the plasma and subsequently the sCD163-Hb-IgG complex is endocytosed into monocytes via FcγR. The endocytosed sCD163 is recycled to restore the homeostasis of CD163 on the monocyte membrane in an autocrine cycle, whereas the internalized Hb is catabolized. Using ex vivo coculture experiments, we demonstrated that the monocyte-derived sCD163 and IgG shuttle residual plasma Hb into the proximal endothelial cells. These findings suggest that CD163 and IgG collaborate to engage monocytes and endothelial cells in a two-pass detoxification mechanism to mount a systemic defense against Hb-induced oxidative stress. 2014-06-13T08:47:57Z 2019-12-06T20:43:02Z 2014-06-13T08:47:57Z 2019-12-06T20:43:02Z 2013 2013 Journal Article Subramanian, K., Du, R., Tan, N. S., Ho, B., & Ding, J. L. (2013). CD163 and IgG Codefend against Cytotoxic Hemoglobin via Autocrine and Paracrine Mechanisms. The Journal of Immunology, 190(10), 5267-5278. 0022-1767 https://hdl.handle.net/10356/101704 http://hdl.handle.net/10220/19771 10.4049/jimmunol.1202648 en The journal of immunology © 2013 The American Association of Immunologists, Inc.
institution Nanyang Technological University
building NTU Library
country Singapore
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences
spellingShingle DRNTU::Science::Biological sciences
Subramanian, Karthik
Du, Ruijuan
Tan, Nguan Soon
Ho, Bow
Ding, Jeak Ling
CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms
description Lysis of RBCs during numerous clinical settings such as severe hemolytic anemia, infection, tissue injury, or blood transfusion releases the endogenous damage-associated molecular pattern, hemoglobin (Hb), into the plasma. The redox-reactive Hb generates cytotoxic reactive oxygen species, disrupting the redox balance and impairing the immune-responsive blood cells. Therefore, it is crucial to understand how the immune system defends against the cytotoxic Hb. We identified a shortcut “capture and quench” mechanism of detoxification of Hb by the monocyte scavenger receptor CD163, independent of the well-known dominant antioxidant, haptoglobin. Our findings support a highly efficient two-pass mechanism of detoxification and clearance of Hb: 1) a direct suppression of Hb-pseudoperoxidase activity by CD163, involving an autocrine loop of CD163 shedding, sequestration of Hb, recycling, and homeostasis of CD163 in human monocytes and 2) paracrine transactivation of endothelial cells by the shedded soluble CD163 (sCD163), which further detoxifies and clears residual Hb. We showed that sCD163 and IgG interact with free Hb in the plasma and subsequently the sCD163-Hb-IgG complex is endocytosed into monocytes via FcγR. The endocytosed sCD163 is recycled to restore the homeostasis of CD163 on the monocyte membrane in an autocrine cycle, whereas the internalized Hb is catabolized. Using ex vivo coculture experiments, we demonstrated that the monocyte-derived sCD163 and IgG shuttle residual plasma Hb into the proximal endothelial cells. These findings suggest that CD163 and IgG collaborate to engage monocytes and endothelial cells in a two-pass detoxification mechanism to mount a systemic defense against Hb-induced oxidative stress.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Subramanian, Karthik
Du, Ruijuan
Tan, Nguan Soon
Ho, Bow
Ding, Jeak Ling
format Article
author Subramanian, Karthik
Du, Ruijuan
Tan, Nguan Soon
Ho, Bow
Ding, Jeak Ling
author_sort Subramanian, Karthik
title CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms
title_short CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms
title_full CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms
title_fullStr CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms
title_full_unstemmed CD163 and IgG codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms
title_sort cd163 and igg codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms
publishDate 2014
url https://hdl.handle.net/10356/101704
http://hdl.handle.net/10220/19771
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