Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice
Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice
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DOI：
10.1172/jci32430
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Apte, Rajendra S.
中科院分区：
文献类型：
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作者：
Kelly, Jennifer;Khan, Aslarn Ali;Apte, Rajendra S.
血管生成异常在心脏病、某些癌症和包括老年性黄斑变性在内的眼科疾病中起着关键作用。巨噬细胞既有抗血管生成的作用，也有促血管生成的作用，在组织损伤部位调节血管生成的作用是关键和复杂的。本研究采用实时荧光定量聚合酶链式反应技术分析了小鼠巨噬细胞细胞因子基因表达谱，并检测了衰老对基因表达和巨噬细胞极化的功能影响。激光损伤视网膜后，18月龄老龄小鼠眼部巨噬细胞中IL-10表达上调，Fas配体(FasL)、IL-12和TNF-α表达下调。巨噬细胞上FasL的下调导致抗血管生成表型的丧失，证明这些巨噬细胞不能抑制血管内皮细胞。我们的结果表明，衰老、FasL和IL-10是巨噬细胞功能的关键决定因素，在包括失明眼病在内的疾病过程中，巨噬细胞功能改变了异常发育后血管的生长。
Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancers, and eye diseases including age-related macular degeneration. Macrophages have been shown previously to be both anti- and proangiogenic, and their role in regulating angiogenesis at sites of tissue injury is critical and complex. In this study, we analyzed cytokine gene expression patterns of mouse macrophages by real-time quantitative PCR and tested the functional effects of senescence on gene expression and macrophage polarization. Following laser injury to the retina, IL-10 was upregulated and Fas ligand (FasL), IL-12, and TNF-alpha were downregulated in ocular macrophages of old mice (>18 months of age). Downregulation of FasL on macrophages led to a loss of the antiangiogenic phenotype, as evidenced by the inability of these macrophages to inhibit vascular endothelial cells. Our results demonstrate that senescence, FasL, and IL-10 are key determinants of macrophage function that alter the growth of abnormal postdevelopmental blood vessels in disease processes including blinding eye disease.