Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification
Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification
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DOI：
10.1182/blood-2008-08-174466
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发表时间：
2009-03-12
期刊：
影响因子：
20.3
通讯作者：
Schaer, Dominik J.
中科院分区：
文献类型：
--
作者：
Buehler, Paul W.;Abraham, Bindu;Schaer, Dominik J.
细胞外血红蛋白(Hb)的解毒和清除被认为是通过CD163清道夫受体途径清除的。然而，即使是低水平的过氧化氢(H_2O_2)暴露也会不可逆转地改变Hb，并通过CD163严重损害Hb的内吞作用。我们在这里表明，当Hb与高亲和力的Hb清道夫蛋白结合时，该复合体通过防止α-珠蛋白交联和β-珠蛋白链关键区域的氨基酸(例如Trp15、Cys93和Cys112)的氧化来保护Hb免受结构修饰。这种结构稳定的结果是，过氧化氢暴露的HB-HP与CD163结合的亲和力与未氧化的络合物相同。表达CD163的细胞对氧化型Hb-Hp的吞噬和溶酶体转位与未表达的复合体一样有效。Hp复合体的形成没有改变Hb通过氧化还原循环消耗添加的过氧化氢的能力，这表明在复合体中氧化自由基的负担转移到了Hp。我们提供了结构和功能证据，证明Hp在过氧化氢氧化挑战时保护Hb，在氧化应激条件下保护CD163介导的Hb清除。此外，我们的数据提供了体内证据，表明未结合的Hb在血管外间隔内被氧化修饰，这与我们的体外研究结果一致。(血。2009；113：2578-2586)
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)