Coronary Intraplaque Hemorrhage Evokes a Novel Atheroprotective Macrophage Phenotype
Coronary Intraplaque Hemorrhage Evokes a Novel Atheroprotective Macrophage Phenotype
复制标题
DOI：
10.2353/ajpath.2009.080431
复制
发表时间：
2009-03-01
影响因子：
6
通讯作者：
Haskard, Dorian O.
中科院分区：
文献类型：
--
作者：
Boyle, Joseph J.;Harrington, Heather A.;Haskard, Dorian O.
斑块内出血通过氧化应激加速动脉粥样硬化，并促进病变发展和不稳定。正常情况下，巨噬细胞通过CD 163介导血红蛋白-触珠蛋白（HbHp）复合物，该过程引起抗炎动脉粥样硬化保护细胞因子白细胞介素（IL）-10的分泌。因此，我们检验了HbHp复合物可能驱动单核细胞分化为动脉粥样硬化保护表型的假设。在动脉粥样硬化斑块中巨噬细胞表型的检查揭示了一种新的血管相关的巨噬细胞群体（HA-mac），其定义为高水平的CD 163，但低水平的人白细胞抗原-DR。RA-mac含有更多的铁，一种促氧化剂催化剂，但矛盾的是氧化损伤较少，通过8-氧代鸟苷含量测定。分化的单核细胞与HbHp复合物在体外再现了CD 163（高）人类白细胞抗原-DR（低）HA-mac表型。这些体外RA-mac细胞更快地清除Hb，并且始终显示出更少的过氧化氢释放、高活性氧和氧化应激，以及增加的存活。通过中和IL-10抗体防止分化为HA-mac，表明IL-10介导该系统中的自分泌反馈机制。非线性动力学模型显示IL-10/CD 163正反馈环驱动离散的RA-mac谱系。模拟进一步指示在HbHp的阈值水平下向HA-mac的全或无转换，并且该转换被实验验证。这些数据证明了一种新的动脉粥样硬化保护性（HA-mac）巨噬细胞亚群的产生，以响应斑块内出血，并提高了治疗性复制这种巨噬细胞表型可能是心脏保护性的动脉粥样硬化的情况下的可能性。(Am J Pathol 2009，174：1097-1108; DOI：10.2353/ajpath.2009.080431）
Intraplaque hemorrhage accelerates atherosclerosis via oxidant stress and contributes to lesion development and destabilization. Normally, macrophages scavenge hemoglobin-haptoglobin (HbHp) complexes via CD163, and this process provokes the secretion of the anti-inflammatory atheroprotective cytokine interleukin (IL)-10. We therefore tested the hypothesis that HbHp complexes may drive monocyte differentiation to an atheroprotective phenotype. Examination of the macrophage phenotype in hemorrhaged atherosclerotic plaques revealed a novel hemorrhage-associated macrophage population (HA-mac), defined by high levels of CD163, but low levels of human leukocyte antigen-DR. RA-mac contained more iron, a pro-oxidant catalyst, but paradoxically had less oxidative injury, measured by 8-oxoguanosine content. Differentiating monocytes with HbHp complexes reproduced the CD163(high) human leukocyte antigen-DR(low) HA-mac phenotype in vitro. These in vitro RA-mac cells cleared Hb more quickly, and consistently showed less hydrogen peroxide release, highly reactive oxygen species and oxidant stress, and Increased survival. Differentiation to HA-mac was prevented by neutralizing IL-10 antibodies, indicating that IL-10 mediates an autocrine feedback mechanism in this system. Nonlinear dynamic modeling showed that an IL-10/CD163-positive feedback loop drove a discrete RA-mac lineage. Simulations further indicated an all-or-none switch to HA-mac at threshold levels of HbHp, and this conversion was experimentally verified. These data demonstrate the creation of a novel atheroprotective (HA-mac) macrophage subpopulation in response to Intraplaque hemorrhage and raise the possibility that therapeutically reproducing this macrophage phenotype may be cardio-protective In cases of atherosclerosis. (Am J Pathol 2009, 174:1097-1108; DOI: 10.2353/ajpath.2009.080431)