Reduction of atherosclerosis in mice by inhibition of CD40 signalling
Reduction of atherosclerosis in mice by inhibition of CD40 signalling
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作者：
Mach, F;Schönbeck, U;Libby, P
越来越多的证据支持炎症和免疫参与动脉粥样硬化的形成（1-4），但动脉粥样硬化斑块中主要细胞类型之间的通讯介质尚未明确。人类动脉粥样硬化病变细胞表达免疫介质CD40及其配体CD40L（也称为CD154或gp39）(5)。CD40与CD40L的相互作用在体液和细胞介导的免疫应答中都占有重要地位(6)。cd4ol阳性T细胞在动脉粥样硬化中积累(5)，并且由于其早期出现、持续存在以及在病变生长和并发症部位的定位，活化的T细胞可能协调动脉粥样硬化发生的重要方面（7-9）。抗cd40l抗体阻断CD40L-CD40信号通路限制实验性自身免疫性疾病，如胶原诱导的关节炎、狼疮肾炎、急性或慢性移植物抗宿主病、多发性硬化症和甲状腺炎（10-14）。体外将CD40连接在动脉粥样硬化相关细胞上可以激活与动脉粥样硬化相关的功能，包括诱导促炎细胞因子(5)、基质金属蛋白酶（15,16）、粘附分子（17-19）和组织因子（16,20）。然而，CD40信号在体内动脉粥样硬化中的作用仍然未知。在这里，我们确定CD40信号的中断是否会影响体内高脂血症小鼠的动脉粥样硬化。用抗小鼠CD40L抗体治疗缺乏低密度脂蛋白受体的小鼠，在喂食高胆固醇饮食12周后，动脉粥样硬化得到限制。抗cd40l抗体可使主动脉粥样硬化病变面积减少59%，脂质含量减少79%。此外，抗cd40l抗体处理的小鼠动脉粥样硬化中巨噬细胞（64%）和T淋巴细胞（70%）明显减少，血管细胞粘附分子-1表达降低。这些数据支持炎症通路参与动脉粥样硬化，并表明CD40信号在高脂血症小鼠动脉粥样硬化过程中的作用。
Increasing amounts of evidence support the involvement of inflammation and immunity in atherogenesis(1-4), but mediators of communication between the major cell types in atherosclerotic plaques are poorly defined. Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand CD40L (also known as CD154 or gp39)(5). The interaction of CD40 with CD40L figures prominently in both humoral and cell-mediated immune responses(6). CD4OL-positive T cells accumulate in atheroma(5), and, by virtue of their early appearance, persistence and localization at sites of lesion growth and complication, activated T cells may coordinate important aspects of atherogenesis(7-9). Interruption of CD40L-CD40 signalling by administration of an anti-CD40L antibody Limits experimental autoimmune diseases such as collagen-induced arthritis, lupus nephritis, acute or chronic graft-versus-host disease, multiple sclerosis and thyroiditis(10-14). Ligation of CD40 on atheroma-associated cells in vitro activates functions related to atherogenesis, including induction of proinflammatory cytokines(5), matrix metalloproteinases(15,16), adhesion molecules(17-19) and tissue factor(16,20). However, the role of CD40 signalling in atherogenesis in vivo remains unknown. Here we determine whether interruption of CD40 signalling influences atherogenesis in vivo in hyperlipidaemic mice, Treatment with antibody against mouse CD40L limited atherosclerosis in mice lacking the receptor for low-density lipoprotein that had been fed a high-cholesterol diet for 12 weeks. This antibody reduces the size of aortic atherosclerotic lesions by 59% and their lipid content by 79%, Furthermore, atheroma of mice treated with anti-CD40L antibody contained significantly fewer macrophages (64%) and T lymphocytes (70%), and exhibited decreased expression of vascular cell adhesion molecule-1. These data support the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice.