Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
Medizinische Klinik 4, Nephrologie, Goethe-Universität Frankfurt, Frankfurt am Main, Germany.
Front Immunol. 2023 Aug 28;14:1252384. doi: 10.3389/fimmu.2023.1252384. eCollection 2023.
The interleukin-1 (IL-1) family and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contribute to atherogenesis but the underlying mechanisms are incompletely understood. Unlike IL-1β, IL-1α is not dependent on the NLRP3 inflammasome to exert its pro-inflammatory effects. Here, a non-genetic model was applied to characterize the role of IL-1α, IL-1β, and NLRP3 for the pathogenesis of atherosclerosis.
Atherogenesis was induced by gain-of-function PCSK9-AAV8 mutant viruses and feeding of a high-fat western diet (WTD) for 12 weeks in C57Bl6/J wildtype mice (WT) and in Il1a, Nlrp3, and Il1b mice.
PCSK9-Il1a mice showed reduced atherosclerotic plaque area in the aortic root with lower lipid accumulation, while no difference was observed between PCSK9-WT, PCSK9-Nlrp3 and PCSK9-Il1b mice. Serum proteomic analysis showed a reduction of pro-inflammatory cytokines (e.g., IL-1β, IL-6) in PCSK9-Il1a as well as in PCSK9-Nlrp3 and PCSK9-Il1b mice. Bone marrow dendritic cells (BMDC) of PCSK9-WT, PCSK9-Nlrp3, and PCSK9-Il1b mice and primary human monocytes showed translocation of IL-1α to the plasma membrane (csIL-1α) upon stimulation with LPS. The translocation of IL-1α to the cell surface was regulated by myristoylation and increased in mice with hypercholesterolemia. CsIL-1α and IL1R1 protein-protein interaction on endothelial cells induced VCAM1 expression and monocyte adhesion, which was abrogated by the administration of neutralizing antibodies against IL-1α and IL1R1.
The results highlight the importance of IL-1α on the cell surface of circulating leucocytes for the development of atherosclerosis. PCSK9-Il1a mice, but not PCSK9-Nlrp3 or PCSK9-Il1b mice, are protected from atherosclerosis after induction of hypercholesterolemia independent of circulating cytokines. Myristoylation and translocation of IL-1α to the cell surface in myeloid cells facilitates leukocyte adhesion and contributes to the development of atherosclerosis.
白细胞介素-1（IL-1）家族和 NOD、LRR 和富含亮氨酸重复序列蛋白 3（NLRP3）炎性小体参与动脉粥样硬化的形成，但其中的潜在机制尚不完全清楚。与 IL-1β不同，IL-1α发挥其促炎作用不依赖于 NLRP3 炎性小体。在此，应用一种非遗传模型来描述 IL-1α、IL-1β 和 NLRP3 在动脉粥样硬化发病机制中的作用。
通过给予载脂蛋白 B 剪接酶 9（PCSK9）-AAV8 突变病毒和高脂西方饮食（WTD）喂养 12 周，在 C57Bl6/J 野生型（WT）小鼠和 Il1a、Nlrp3 和 Il1b 小鼠中诱导动脉粥样硬化形成。
PCSK9-Il1a 小鼠主动脉根部的动脉粥样硬化斑块面积减少，脂质蓄积减少，而 PCSK9-WT、PCSK9-Nlrp3 和 PCSK9-Il1b 小鼠之间无差异。血清蛋白质组学分析显示，PCSK9-Il1a 以及 PCSK9-Nlrp3 和 PCSK9-Il1b 小鼠中促炎细胞因子（如 IL-1β、IL-6）减少。PCSK9-WT、PCSK9-Nlrp3 和 PCSK9-Il1b 小鼠的骨髓树突状细胞（BMDC）和原代人单核细胞在受到脂多糖刺激时，IL-1α向质膜易位（csIL-1α）。胆固醇血症小鼠中 IL-1α 的质膜易位受豆蔻酰化调节并增加。csIL-1α 和内皮细胞上的 IL1R1 蛋白-蛋白相互作用诱导 VCAM1 表达和单核细胞黏附，而中和抗 IL-1α 和 IL1R1 抗体可阻断此作用。
这些结果强调了循环白细胞表面 IL-1α在动脉粥样硬化发展中的重要性。在诱导高胆固醇血症后，PCSK9-Il1a 小鼠而非 PCSK9-Nlrp3 或 PCSK9-Il1b 小鼠可免受动脉粥样硬化的影响，而不受循环细胞因子的影响。髓样细胞中 IL-1α 的豆蔻酰化和质膜易位有助于白细胞黏附，促进动脉粥样硬化的发展。
