Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment.
Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment.
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DOI：
10.1161/circulationaha.116.024790
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发表时间：
2016-10-18
期刊：
影响因子：
37.8
通讯作者：
Soehnlein O
中科院分区：
文献类型：
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作者：
Ortega-Gomez A;Salvermoser M;Rossaint J;Pick R;Brauner J;Lemnitzer P;Tilgner J;de Jong RJ;Megens RT;Jamasbi J;Döring Y;Pham CT;Scheiermann C;Siess W;Drechsler M;Weber C;Grommes J;Zarbock A;Walzog B;Soehnlein O
在动脉粥样硬化背景下，针对动脉白细胞募集的治疗目标在临床研究中一直令人失望。此类失败的原因包括缺乏对动脉特异性募集模式的了解。在这里，我们确定了组织蛋白酶 G (CatG) 在动脉骨髓细胞募集过程中的重要性。对 Apoe−/− 和 CatG 缺陷小鼠 (Apoe−/−Ctsg−/−) 的颈动脉、颈静脉、提睾小动脉和小静脉进行活体显微镜检查，用于研究高脂饮食喂养或肿瘤坏死因子刺激后的位点特异性骨髓细胞行为。高脂肪饮食 4 周后，在主动脉根部切片中评估动脉粥样硬化的发展，而在吸入脂多糖后评估肺部炎症。使用 2 光子和共焦显微镜对整体制备物中 CatG 和 CCL5 的内皮沉积进行定量。我们的观察阐明了 CatG 在动脉白细胞粘附过程中的关键作用，而在小静脉粘附过程中未发现这种作用。因此，CatG 缺乏会减轻动脉粥样硬化，但不会减轻急性肺部炎症。从机制上讲，CatG 固定在动脉内皮上，激活白细胞以牢固地粘附整合素簇，这是在高剪切流下实现有效粘附的至关重要的过程。 CatG 的治疗性中和可特异性消除动脉白细胞粘附，而不影响微循环中的骨髓细胞粘附。重复应用 CatG 中和抗体可以抑制小鼠动脉粥样硬化形成。总而言之，这些发现提供了以 CatG 指导的粘附强化为中心的动脉特异性募集模式的证据。抑制这一过程可以为治疗动脉炎症提供一种新的策略，且副作用有限。
Therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis has been disappointing in clinical studies. Reasons for such failures include the lack of knowledge of arterial-specific recruitment patterns. Here we establish the importance of the cathepsin G (CatG) in the context of arterial myeloid cell recruitment. Intravital microscopy of the carotid artery, the jugular vein, and cremasteric arterioles and venules in Apoe−/− and CatG-deficient mice (Apoe−/−Ctsg−/−) was used to study site-specific myeloid cell behavior after high-fat diet feeding or tumor necrosis factor stimulation. Atherosclerosis development was assessed in aortic root sections after 4 weeks of high-fat diet, whereas lung inflammation was assessed after inhalation of lipopolysaccharide. Endothelial deposition of CatG and CCL5 was quantified in whole-mount preparations using 2-photon and confocal microscopy. Our observations elucidated a crucial role for CatG during arterial leukocyte adhesion, an effect not found during venular adhesion. Consequently, CatG deficiency attenuates atherosclerosis but not acute lung inflammation. Mechanistically, CatG is immobilized on arterial endothelium where it activates leukocytes to firmly adhere engaging integrin clustering, a process of crucial importance to achieve effective adherence under high-shear flow. Therapeutic neutralization of CatG specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of CatG-neutralizing antibodies permitted inhibition of atherogenesis in mice. Taken together, these findings present evidence of an arterial-specific recruitment pattern centered on CatG-instructed adhesion strengthening. The inhibition of this process could provide a novel strategy for treatment of arterial inflammation with limited side effects.