Laboratory of Immunobiology, Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece.
J Intern Med. 2020 Sep;288(3):321-334. doi: 10.1111/joim.13085. Epub 2020 May 14.
The interplay between innate and adaptive immunity is central in life-threatening clinical complications of atherosclerosis such as myocardial infarction and stroke. The specific mechanisms involved and their protective versus detrimental effects in the disease process remain poorly understood. We have previously shown that higher levels of Toll-like receptor 7 (TLR7) expression in human atherosclerotic lesions are correlated with better patient outcome.
In this study, we explored whether TLR7 activation can ameliorate disease in experimental atherosclerosis in mice.
Apolipoprotein E deficient mice (Apoe ) with established disease were injected for five weeks intraperitoneally with the TLR7 ligand R848. Local effects were evaluated by characterization of the lesion. Systemic effects of the treatment were investigated by immune composition analysis in the spleen and plasma measurements.
The in vivo treatment arrested lesion progression in the aorta. We also detected expansion of marginal zone B cells and T in the spleen together with increased plasma IgM antibodies against oxidized low-density lipoprotein (oxLDL) and reduced plasma cholesterol levels. These changes were accompanied by increased accumulation of IgM antibodies, decreased necrosis and fewer apoptotic cells in atherosclerotic lesions.
Our findings show that TLR7 stimulation could ameliorate atherosclerotic lesion burden and reduce plasma cholesterol in Apoe mice. TLR7 stimulation was associated with an atheroprotective B-cell and T response, which may have systemic and local effects within lesions that could prevent arterial lipid accumulation and inflammation.
先天免疫和适应性免疫的相互作用是导致动脉粥样硬化危及生命的临床并发症（如心肌梗死和中风）的核心。然而，其中涉及的具体机制及其在疾病过程中的保护作用或有害作用仍知之甚少。我们之前的研究表明，人类动脉粥样硬化病变中 Toll 样受体 7（TLR7）表达水平较高与患者预后较好相关。
在本研究中，我们探讨了 TLR7 激活是否可以改善实验性动脉粥样硬化小鼠的疾病。
用 TLR7 配体 R848 经腹腔注射五周，对已建立疾病的载脂蛋白 E 缺陷型（Apoe）小鼠进行处理。通过病变特征来评估局部作用，通过脾脏和血浆测量的免疫成分分析来研究治疗的全身作用。
体内治疗可阻止主动脉中的病变进展。我们还检测到脾脏中边缘区 B 细胞和 T 细胞的扩增，同时伴有氧化型低密度脂蛋白（oxLDL）的血浆 IgM 抗体增加和血浆胆固醇水平降低。这些变化伴随着 IgM 抗体的积累增加、坏死减少和动脉粥样硬化病变中凋亡细胞减少。
我们的研究结果表明，TLR7 刺激可减轻 Apoe 小鼠的动脉粥样硬化病变负担并降低血浆胆固醇水平。TLR7 刺激与动脉粥样硬化保护作用的 B 细胞和 T 细胞反应相关，可能在病变内具有全身和局部作用，从而阻止动脉脂质积累和炎症。
