Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification

被引：156

作者：

Buehler, Paul W. ^{[1
]}

Abraham, Bindu ^{[1
]}

Vallelian, Florence ^{[2
]}

Linnemayr, Charlotte ^{[2
]}

Pereira, Claudia P. ^{[2
]}

Cipollo, John F. ^{[1
]}

Jia, Yiping ^{[1
]}

Mikolajczyk, Malgorzata ^{[1
]}

Boretti, Felicitas S. ^{[3
]}

Schoedon, Gabriele ^{[2
]}

Alayash, Abdu I. ^{[1
]}

Schaer, Dominik J. ^{[2
]}

机构：

[1] US FDA, CBER, Washington, DC 20204 USA

[2] Univ Zurich, Div Internal Med, Zurich, Switzerland

[3] Univ Zurich, Clin Small Anim Internal Med, Vetsuisse Fac, Zurich, Switzerland

来源：

BLOOD | 2009年 / 113卷 / 11期

基金：

瑞士国家科学基金会;

关键词：

SPERM-WHALE MYOGLOBIN; HYDROGEN-PEROXIDE; BINDING-SITE; OXIDATIVE STRESS; REDOX PROPERTIES; OXYGEN-BINDING; CROSS-LINKING; ALPHA-CHAIN; HEME UPTAKE; RECEPTOR;

D O I：

10.1182/blood-2008-08-174466

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Detoxification and clearance of extracellular hemoglobin (Hb) have been attributed to its removal by the CD163 scavenger receptor pathway. However, even low-level hydrogen peroxide (H2O2) exposure irreversibly modifies Hb and severely impairs Hb endocytosis by CD163. We show here that when Hb is bound to the high-affinity Hb scavenger protein haptoglobin (Hp), the complex protects Hb from structural modification by preventing alpha-globin cross-links and oxidations of amino acids in critical regions of the beta-globin chain (eg, Trp15, Cys93, and Cys112). As a result of this structural stabilization, H2O2-exposed Hb-Hp binds to CD163 with the same affinity as nonoxidized complex. Endocytosis and lysosomal translocation of oxidized Hb-Hp by CD163-expressing cells were found to be as efficient as with nonoxidized complex. Hp complex formation did not alter Hb's ability to consume added H2O2 by redox cycling, suggesting that within the complex the oxidative radical burden is shifted to Hp. We provide structural and functional evidence that Hp protects Hb when oxidatively challenged with H2O2 preserving CD163-mediated Hb clearance under oxidative stress conditions. In addition, our data provide in vivo evidence that unbound Hb is oxidatively modified within extravascular compartments consistent with our in vitro findings. (Blood. 2009;113:2578-2586)

引用

页码：2578 / 2586

页数：9

共 58 条

[1] CD163-mediated hemoglobin-heme uptake activates macrophage HO-1, providing an antiinflammatory function [J].