Hematopoietic Interferon Regulatory Factor 8-Deficiency Accelerates Atherosclerosis in Mice
Hematopoietic Interferon Regulatory Factor 8-Deficiency Accelerates Atherosclerosis in Mice
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DOI：
10.1161/atvbaha.111.236539
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发表时间：
2012-07-01
影响因子：
8.7
通讯作者：
Zernecke, Alma
中科院分区：
文献类型：
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作者：
Doering, Yvonne;Soehnlein, Oliver;Zernecke, Alma
目的-炎症性白细胞积聚导致动脉粥样硬化。虽然单核细胞/巨噬细胞和嗜多形核白细胞（PMN）有助于病变的形成，骨髓增生性疾病的后遗症仍有待阐明。方法和结果-我们使用的小鼠缺乏干扰素调节因子8（IRF 8（-/-））的造血细胞，发展慢性髓性白血病样表型。与对照组相比，用IRF 8（-/-）或IRF 8（-/-）载脂蛋白E缺陷骨髓重建的载脂蛋白E缺陷小鼠显示动脉粥样硬化病变形成加剧。IRF 8（-/-）骨髓小鼠的慢性粒细胞性白血病样表型，反映了循环中PMN的扩张，与PMN的损伤积累和凋亡增加以及坏死核心扩大有关。IRF 8（-/-）与IRF 8（+/+）PMN相比，其活性氧的形成和PMN颗粒成分的放电均未受影响。相比之下，在炎症部位以相同数量积累，IRF 8（-/-）巨噬细胞在红细胞增多、脂质摄取和白细胞介素-10细胞因子产生方面有缺陷。重要的是，在低密度脂蛋白受体或载脂蛋白E缺陷小鼠与IRF 8（-/-）或IRF 8（-/-）载脂蛋白E缺陷的骨髓废除增加病变formation.Conclusion-These研究结果表明，慢性粒细胞性白血病样表型有助于加速小鼠动脉粥样硬化。在其他细胞类型的促动脉粥样硬化作用中，这部分与功能完整的PMN的扩增有关。（Arterioscler Thromb Vasc Biol.2012;32：1613-1623.）
Objective-Inflammatory leukocyte accumulation drives atherosclerosis. Although monocytes/macrophages and polymorphonuclear neutrophilic leukocytes (PMN) contribute to lesion formation, sequelae of myeloproliferative disease remain to be elucidated.Methods and Results-We used mice deficient in interferon regulatory factor 8 (IRF8(-/-)) in hematopoietic cells that develop a chronic myelogenous leukemia-like phenotype. Apolipoprotein E-deficient mice reconstituted with IRF8(-/-) or IRF8(-/-) apolipoprotein E-deficient bone marrow displayed an exacerbated atherosclerotic lesion formation compared with controls. The chronic myelogenous leukemia-like phenotype in mice with IRF8(-/-) bone marrow, reflected by an expansion of PMN in the circulation, was associated with an increased lesional accumulation and apoptosis of PMN, and enlarged necrotic cores. IRF8(-/-) compared with IRF8(+/+) PMN displayed unaffected reactive oxygen species formation and discharge of PMN granule components. In contrast, accumulating in equal numbers at sites of inflammation, IRF8(-/-)macrophages were defective in efferocytosis, lipid uptake, and interleukin-10 cytokine production. Importantly, depletion of PMN in low-density lipoprotein receptor or apolipoprotein E-deficient mice with IRF8(-/-) or IRF8(-/-) apolipoprotein E-deficient bone marrow abrogated increased lesion formation.Conclusion-These findings indicate that a chronic myelogenous leukemia-like phenotype contributes to accelerated atherosclerosis in mice. Among proatherosclerotic effects of other cell types, this, in part, is linked to an expansion of functionally intact PMN. (Arterioscler Thromb Vasc Biol. 2012;32:1613-1623.)