Treatment with a Toll-like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice
Treatment with a Toll-like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice
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DOI：
10.1111/joim.13085
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发表时间：
2020-05-14
影响因子：
11.1
通讯作者：
Paulsson-Berne，G.
中科院分区：
文献类型：
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作者：
Karadimou，G.;Gistera，A.;Paulsson-Berne，G.
背景先天免疫和适应性免疫之间的相互作用是威胁生命的动脉粥样硬化临床并发症（例如心肌梗塞和中风）的核心。所涉及的具体机制及其在疾病过程中的保护作用与有害作用仍然知之甚少。我们之前已经证明，人类动脉粥样硬化病变中较高水平的 Toll 样受体 7 (TLR7) 表达与更好的患者预后相关。目的在本研究中，我们探讨 TLR7 激活是否可以改善小鼠实验性动脉粥样硬化疾病。方法对已患有疾病的载脂蛋白 E 缺陷小鼠 (Apoe−/−) 腹膜内注射 TLR7 配体 R848，为期五周。通过病变的特征来评估局部效应。通过脾脏中的免疫成分分析和血浆测量来研究治疗的全身效应。结果体内治疗阻止了主动脉的病变进展。我们还检测到边缘区 B 细胞和脾脏 Tregin 的扩张，以及血浆抗氧化低密度脂蛋白 (oxLDL) 的 IgM 抗体增加和血浆胆固醇水平降低。这些变化伴随着动脉粥样硬化病变中IgM抗体积累的增加、坏死的减少和凋亡细胞的减少。结论我们的研究结果表明，TLR7刺激可以改善Apoe−/−小鼠的动脉粥样硬化病变负担并降低血浆胆固醇。 TLR7 刺激与动脉粥样硬化保护 B 细胞和 Tregresponse 相关，这可能在病变内产生全身和局部效应，从而防止动脉脂质积累和炎症。
BackgroundThe 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.ObjectiveIn this study, we explored whether TLR7 activation can ameliorate disease in experimental atherosclerosis in mice.MethodsApolipoprotein 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.ResultsThein vivotreatment arrested lesion progression in the aorta. We also detected expansion of marginal zone B cells and Tregin 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.ConclusionsOur findings show that TLR7 stimulation could ameliorate atherosclerotic lesion burden and reduce plasma cholesterol inApoe−/−mice. TLR7 stimulation was associated with an atheroprotective B‐cell and Tregresponse, which may have systemic and local effects within lesions that could prevent arterial lipid accumulation and inflammation.