Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution
Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution
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DOI：
10.1182/blood-2010-03-272138
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发表时间：
2010-12-23
期刊：
影响因子：
20.3
通讯作者：
Rouault, Tracey A.
中科院分区：
文献类型：
--
作者：
Kovtunovych, Gennadiy;Eckhaus, Michael A.;Rouault, Tracey A.
为了更好地理解先前在缺乏血红素氧化酶-1（HO-1）的人类患者和小鼠中报道的组织铁超载和贫血，我们研究了HO-1(Hmox1)（-/-）小鼠中的铁分布和病理。我们发现HO-1（-/-）小鼠的常驻脾和肝巨噬细胞大部分缺失。在体外实验中，吞噬红细胞导致HO-1（-/-）巨噬细胞死亡，支持HO-1（-/-）巨噬细胞因暴露于吞噬红细胞释放的血红素而死亡的假说。体内HO-1（-/-）巨噬细胞的破裂和非代谢血红素的释放可能引起组织炎症。在老年小鼠中，最初的脾肿大发展为红髓纤维化、萎缩和功能性脾功能减退，再现了ho -1缺陷患者的脾功能缺失。我们推测，组织巨噬细胞清除衰老红细胞的失败导致血管内溶血，血红素和血红蛋白清除蛋白、血凝素和触珠蛋白的表达增加。巨噬细胞缺乏表达触珠蛋白受体CD163，降低了触珠蛋白中和循环血红蛋白的能力，肾近端小管发生铁超载，而肾近端小管能够用HO-2分解血红素。因此，在HO-1（-/-）哺乳动物中，吞噬红细胞的巨噬细胞功能和活力降低是组织损伤和铁再分布的主要原因。（血液，2010;116(26):6054-6062）
To better understand the tissue iron overload and anemia previously reported in a human patient and mice that lack heme oxygenase-1 (HO-1), we studied iron distribution and pathology in HO-1(Hmox1)(-/-) mice. We found that resident splenic and liver macrophages were mostly absent in HO-1(-/-) mice. Erythrophagocytosis caused the death of HO-1(-/-) macrophages in in vitro experiments, supporting the hypothesis that HO-1(-/-) macrophages died of exposure to heme released on erythrophagocytosis. Rupture of HO-1(-/-) macro-phages in vivo and release of nonmetabolized heme probably caused tissue inflammation. In the spleen, initial splenic enlargement progressed to red pulp fibrosis, atrophy, and functional hyposplenism in older mice, recapitulating the asplenia of an HO-1-deficient patient. We postulate that the failure of tissue macrophages to remove senescent erythrocytes led to intravascular hemolysis and increased expression of the heme and hemoglobin scavenger proteins, hemopexin and haptoglobin. Lack of macro-phages expressing the haptoglobin receptor, CD163, diminished the ability of haptoglobin to neutralize circulating hemoglobin, and iron overload occurred in kidney proximal tubules, which were able to catabolize heme with HO-2. Thus, in HO-1(-/-) mammals, the reduced function and viability of erythrophagocytosing macrophages are the main causes of tissue damage and iron redistribution. (Blood. 2010; 116(26):6054-6062)