Yu Yinda, Lin Shiying, Pan Yueyun, He Ning, Wu Yanzhao, Ahmed Osman, Hedin Ulf, Karlsson Mikael C I, Li Nailin, Gisterå Anton
Department of Medicine Solna, Karolinska Institutet, and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
JACC Basic Transl Sci. 2025 Jul 16;10(8):101322. doi: 10.1016/j.jacbts.2025.101322.
Autoimmunity to low-density lipoprotein (LDL) is linked to atherosclerosis, with LDL immunization proposed as a preventive measure, but the mechanisms of atheroprotective immunity are not well understood. We investigated T-cell responses to LDL using 2 T-cell receptor transgenic mouse strains. At 52 weeks, BT1×HuBL mice showed reduced atherosclerosis, increased humoral responses against LDL, and lower plasma cholesterol. Conversely, BT3×HuBL mice had reduced atherosclerosis without changes in cholesterol, linked to increased type 1 regulatory T cells, interleukin (IL)-10 production, and decreased characteristics of plaque stability. In human plaques, IL10 mRNA negatively correlated with collagen content, and IL-10 inhibited collagen production in vitro. We conclude that atheroprotective LDL immunity elicits 2 distinct pathways: lipid-lowering immune responses and local anti-inflammatory IL-10 production. Because IL-10 is associated with decreased plaque stability and increased risk of cardiovascular events, treatments aimed at promoting IL-10 signaling over extended periods to reduce vascular inflammation should be carefully monitored.
对低密度脂蛋白（LDL）的自身免疫与动脉粥样硬化有关，有人提出将LDL免疫作为一种预防措施，但动脉粥样硬化保护性免疫的机制尚未完全了解。我们使用两种T细胞受体转基因小鼠品系研究了T细胞对LDL的反应。在52周时，BT1×HuBL小鼠的动脉粥样硬化减轻，针对LDL的体液反应增加，血浆胆固醇降低。相反，BT3×HuBL小鼠的动脉粥样硬化减轻，但胆固醇没有变化，这与1型调节性T细胞增加、白细胞介素（IL）-10产生以及斑块稳定性特征降低有关。在人类斑块中，IL10 mRNA与胶原蛋白含量呈负相关，并且IL-10在体外抑制胶原蛋白的产生。我们得出结论，动脉粥样硬化保护性LDL免疫引发两种不同的途径：降低血脂的免疫反应和局部抗炎性IL-10的产生。由于IL-10与斑块稳定性降低和心血管事件风险增加有关，因此对于旨在长期促进IL-10信号传导以减轻血管炎症的治疗应进行仔细监测。
