Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA.
Circulation. 2011 Dec 20;124(25):2933-43. doi: 10.1161/CIRCULATIONAHA.111.034850. Epub 2011 Nov 21.
The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood.
Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune-activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed with the use of mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortas and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using apolipoprotein E-deficient mouse models, we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions.
The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.
免疫系统与异常代谢状况之间的相互作用维持并加剧了慢性炎症和代谢功能障碍的恶性循环，这对于动脉粥样硬化的进展至关重要。众所周知，异常代谢状况，如血脂异常和高血糖，会引起各种细胞应激反应，导致组织炎症和免疫细胞激活，进而使代谢功能障碍恶化。然而，连接这些过程的分子事件尚不清楚。
检查了患有高血糖和高血脂的人类和小鼠的组织和器官中 NKG2D 的配体表达，NKG2D 是几种免疫细胞表达的一种有效的免疫激活受体，并用缺乏 NKG2D 的小鼠或用单克隆抗体阻断 NKG2D 来研究 NKG2D 在动脉粥样硬化和代谢疾病中的作用。NKG2D 配体在多个器官中上调，特别是在动脉粥样硬化的主动脉和发炎的肝脏中。体外培养时，异常代谢物与代谢功能障碍相关诱导配体上调。使用载脂蛋白 E 缺陷型小鼠模型，我们证明了预防 NKG2D 功能会导致斑块形成显著减少，抑制多种免疫细胞类型介导的全身和器官炎症，并缓解异常代谢状况。
NKG2D/配体相互作用是慢性炎症和代谢功能障碍恶性循环中的一个关键分子环节，它促进了动脉粥样硬化的发生，可能成为该疾病治疗干预的一个有用靶点。
