Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7491, Norway;
J Immunol. 2014 Mar 15;192(6):2837-45. doi: 10.4049/jimmunol.1302484. Epub 2014 Feb 19.
Inflammation is associated with development of atherosclerosis, and cholesterol crystals (CC) have long been recognized as a hallmark of atherosclerotic lesions. CC appear early in the atheroma development and trigger inflammation by NLRP3 inflammasome activation. In this study we hypothesized whether CC employ the complement system to activate inflammasome/caspase-1, leading to release of mature IL-1β, and whether complement activation regulates CC-induced cytokine production. In this study we describe that CC activated both the classical and alternative complement pathways, and C1q was found to be crucial for the activation. CC employed C5a in the release of a number of cytokines in whole blood, including IL-1β and TNF. CC induced minimal amounts of cytokines in C5-deficient whole blood, until reconstituted with C5. Furthermore, C5a and TNF in combination acted as a potent primer for CC-induced IL-1β release by increasing IL-1β transcripts. CC-induced complement activation resulted in upregulation of complement receptor 3 (CD11b/CD18), leading to phagocytosis of CC. Also, CC mounted a complement-dependent production of reactive oxygen species and active caspase-1. We conclude that CC employ the complement system to induce cytokines and activate the inflammasome/caspase-1 by regulating several cellular responses in human monocytes. In light of this, complement inhibition might be an interesting therapeutic approach for treatment of atherosclerosis.
炎症与动脉粥样硬化的发展有关，胆固醇晶体 (CC) 长期以来一直被认为是动脉粥样硬化病变的标志。CC 在动脉粥样硬化的早期出现，并通过 NLRP3 炎性体激活引发炎症。在这项研究中，我们假设 CC 是否利用补体系统激活炎性体/半胱天冬酶-1，导致成熟的 IL-1β释放，以及补体激活是否调节 CC 诱导的细胞因子产生。在这项研究中，我们描述了 CC 激活了经典和替代补体途径，并且发现 C1q 对于激活至关重要。CC 在全血中释放了许多细胞因子，包括 IL-1β 和 TNF，C5a 也参与其中。CC 在 C5 缺陷的全血中诱导产生的细胞因子数量很少，直到用 C5 重建。此外，C5a 和 TNF 联合作用可作为 CC 诱导的 IL-1β 释放的有效启动子，通过增加 IL-1β 转录物来实现。CC 诱导的补体激活导致补体受体 3 (CD11b/CD18) 的上调，从而导致 CC 的吞噬作用。此外，CC 还引发了补体依赖性的活性氧和活性 caspase-1 的产生。我们得出结论，CC 通过调节人单核细胞中的几种细胞反应，利用补体系统诱导细胞因子并激活炎性体/半胱天冬酶-1。有鉴于此，补体抑制可能是治疗动脉粥样硬化的一种有趣的治疗方法。
