Interruption of classic CD40L-CD40 signalling but not of the novel CD40L-Mac-1 interaction limits arterial neointima formation in mice
Interruption of classic CD40L-CD40 signalling but not of the novel CD40L-Mac-1 interaction limits arterial neointima formation in mice
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DOI：
10.1160/th13-08-0653
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发表时间：
2014-03
影响因子：
6.7
通讯作者：
F. Willecke;Shilpa Tiwari;Benjamin Rupprecht;D. Wolf;S. Hergeth;N. Hoppe;B. Dufner;Lisa Schulte;N. Michel;N. Bukosza;T. Marchini;Markus Jäckel;P. Stachon;I. Hilgendorf;Katharina Zeschky;Rebecca Schleicher;H. Langer;C. von zur Muhlen;C. Bode;K. Peter;A. Zirlik
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作者：
F. Willecke;Shilpa Tiwari;Benjamin Rupprecht;D. Wolf;S. Hergeth;N. Hoppe;B. Dufner;Lisa Schulte;N. Michel;N. Bukosza;T. Marchini;Markus Jäckel;P. Stachon;I. Hilgendorf;Katharina Zeschky;Rebecca Schleicher;H. Langer;C. von zur Muhlen;C. Bode;K. Peter;A. Zirlik
共刺激免疫分子CD 40 L在包括动脉疾病在内的各种炎症性疾病中表现突出。最近，我们取得了令人惊讶的发现，CD 40 L介导的动脉粥样硬化形成独立于其经典受体CD 40通过一种新的相互作用与白细胞整合素Mac-1。在此，我们假设选择性阻断CD 40 L-Mac-1相互作用也可延缓再狭窄。我们通过结扎左颈动脉诱导C57/BL 6小鼠的新生内膜形成。将小鼠随机分配至每天腹膜内注射选择性抑制CD 40 L-Mac-1相互作用的小肽cM 7、乱序对照肽scM 7或盐水，持续28天。有趣的是，cM 7处理的小鼠与接受对照肽或生理盐水的小鼠相比产生了相似大小的新生内膜，如通过组织学横截面的计算机辅助分析所评估的。这些数据表明，CD 40 L-Mac-1相互作用不是再狭窄发生所必需的。相比之下，与相应的野生型对照组相比，平行进行颈动脉结扎的CD 40缺陷小鼠的新生内膜病变显著减少（2872 ± 843 µm² vs 35469 ± 11870 µm²）。CD 40缺陷小鼠的流式细胞术显示血小板-粒细胞和血小板-炎性单核细胞聚集体的形成减少。在体外，CD 40缺陷型血小板-白细胞聚集体的上清液减弱平滑肌细胞的增殖并增加平滑肌细胞的凋亡。与动脉粥样硬化不同，CD 40 L通过其经典受体CD 40介导新生内膜形成，而不是通过其最近描述的与Mac-1的新型相互作用。因此，选择性靶向CD 40 L-Mac-1结合似乎不是对抗再狭窄的有利策略。
Summary The co-stimulatory immune molecule CD40L figures prominently in a variety of inflammatory conditions including arterial disease. Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1. Here, we hypothesised that selective blockade of the CD40L-Mac-1 interaction may also retard restenosis. We induced neointima formation in C57/BL6 mice by ligation of the left carotid artery. Mice were randomised to daily intraperitoneal injections of either cM7, a small peptide selectively inhibiting the CD40L-Mac-1 interaction, scM7, a scrambled control peptide, or saline for 28 days. Interestingly, cM7-treated mice developed neointima of similar size compared with mice receiving the control peptide or saline as assessed by computer-assisted analysis of histological cross sections. These data demonstrate that the CD40L-Mac-1 interaction is not required for the development of restenosis. In contrast, CD40-deficient mice subjected to carotid ligation in parallel, developed significantly reduced neointimal lesions compared with respective wild-type controls (2872 ± 843 µm² vs 35469 ± 11870 µm²). Flow cytometry in CD40-deficient mice revealed reduced formation of platelet-granulocyte and platelet-inflammatory monocyte-aggregates. In vitro, supernatants of CD40-deficient platelet-leukocyte aggregates attenuated proliferation and increased apoptosis of smooth muscle cells. Unlike in the setting of atherosclerosis, CD40L mediates neointima formation via its classic receptor CD40 rather than via its recently described novel interaction with Mac-1. Therefore, selective targeting of CD40L-Mac-1 binding does not appear to be a favorable strategy to fight restenosis.