Interleukin-18 Amplifies Macrophage Polarization and Morphological Alteration, Leading to Excessive Angiogenesis.
Interleukin-18 Amplifies Macrophage Polarization and Morphological Alteration, Leading to Excessive Angiogenesis.
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DOI：
10.3389/fimmu.2018.00334
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发表时间：
2018
影响因子：
7.3
通讯作者：
Takahashi H
中科院分区：
文献类型：
--
作者：
Kobori T;Hamasaki S;Kitaura A;Yamazaki Y;Nishinaka T;Niwa A;Nakao S;Wake H;Mori S;Yoshino T;Nishibori M;Takahashi H
M2巨噬细胞（Mφ）通过释放促血管生成介质或在几种慢性炎症性疾病的微环境中与内皮细胞直接相互作用促进病理性血管生成，包括类风湿关节炎和癌症，其中白细胞介素(IL)-18也有助于过度血管生成。然而，具体机制尚不清楚。本研究以小鼠m - φ样细胞系RAW264.7细胞和小鼠内皮细胞系b.m end5细胞为实验对象，探讨在含有IL-18的微环境下M2 - m - φs诱导血管过度生成的机制。我们发现IL-18与IL-10协同作用，放大Mφ衍生介质如骨桥蛋白（OPN）和凝血酶的产生，产生凝血酶裂解形式的OPN，通过整合素α4/α9起作用，从而增强Mφ的M2极化，并增加表面CD163表达，与形态学改变相关。此外，观察血管生成过程中m - φs的时间行为和形态改变的结果表明，m2样m - φs通过与内皮细胞的直接细胞-细胞相互作用诱导过度血管生成，可能是由CD163介导的。
M2 macrophage (Mφ) promotes pathologic angiogenesis through a release of pro-angiogenic mediators or the direct cell–cell interaction with endothelium in the micromilieu of several chronic inflammatory diseases, including rheumatoid arthritis and cancer, where interleukin (IL)-18 also contributes to excessive angiogenesis. However, the detailed mechanism remains unclear. The aim of this study is to investigate the mechanism by which M2 Mφs in the micromilieu containing IL-18 induce excessive angiogenesis in the in vitro experimental model using mouse Mφ-like cell line, RAW264.7 cells, and mouse endothelial cell line, b.End5 cells. We discovered that IL-18 acts synergistically with IL-10 to amplify the production of Mφ-derived mediators like osteopontin (OPN) and thrombin, yielding thrombin-cleaved form of OPN generation, which acts through integrins α4/α9, thereby augmenting M2 polarization of Mφ with characteristics of increasing surface CD163 expression in association with morphological alteration. Furthermore, the results of visualizing temporal behavior and morphological alteration of Mφs during angiogenesis demonstrated that M2-like Mφs induced excessive angiogenesis through the direct cell–cell interaction with endothelial cells, possibly mediated by CD163.