Pristane attenuates atherosclerosis in Apoe-/- mice via IL-4-secreting regulatory plasma cell-mediated M2 macrophage polarization
Pristane attenuates atherosclerosis in Apoe-/- mice via IL-4-secreting regulatory plasma cell-mediated M2 macrophage polarization
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降植烷通过分泌 IL-4 的调节性浆细胞介导的 M2 巨噬细胞极化减轻 Apoe-/- 小鼠的动脉粥样硬化
DOI：
10.1016/j.biopha.2022.113750
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发表时间：
2022-09-29
影响因子：
7.5
通讯作者：
Dai，Xiaoyan
中科院分区：
文献类型：
--
作者：
Huang，Yimin;Ma，Kongyang;Dai，Xiaoyan
动脉粥样硬化是一种炎症性进行性血管疾病，在世界范围内导致心脏病和中风。具有免疫抑制功能的B细胞与自身免疫、炎症和心血管疾病有关。然而，调节性B细胞在动脉粥样硬化中的确切作用以及与巨噬细胞的相互作用仍不清楚。在我们的研究中，8周龄的雌性载脂蛋白E零(apoE−/−)小鼠被单剂量的赋形剂或普瑞斯坦处理，然后被放置在致动脉粥样硬化的饮食中12周。我们发现，在载脂蛋白−/−小鼠中，Pristane减少了动脉粥样硬化病变的形成，并增加了动脉粥样硬化斑块的稳定性。我们还观察到用普瑞斯坦治疗的−/−小鼠CD19+B细胞比例降低，而CD138+浆细胞和CD206+M2巨噬细胞比例升高。重要的是，Pristane抑制免疫细胞向血管壁的渗透。−/−小鼠骨髓CD138+浆细胞经Pristane处理后IL-4表达上调。在体外，氧化型低密度脂蛋白(OxLDL)可直接诱导分泌IL-4的浆细胞生成。在抗IL-4中和抗体的共培养体系中，结果表明oxLDL诱导的CD138+浆细胞可通过分泌IL-4促进M2巨噬细胞极化。我们的数据显示了一个意想不到的作用，即Pristane诱导产生IL-4的CD138+调节性浆细胞生成和M2极化，以保护动脉粥样硬化的发展。
Atherosclerosis, an inflammatory progressive vascular disease, causes heart disease and stroke worldwide. B cells with immune suppressive functions have been implicated in autoimmune, inflammatory, and cardiovascular diseases. However, the precise role of regulatory B cells and the interaction with macrophages in atherosclerosis remains undefined. In our study, eight-week-old female apolipoprotein E null (Apoe−/−) mice were treated with a single dose of vehicle or pristane and then placed on an atherogenic diet for 12 weeks. We found that pristane decreased atherosclerotic lesion formation and increased stability of atherosclerotic plaques inApoe−/−mice. We also observed lower frequencies of CD19+B cells but higher frequencies of CD138+plasma cells and CD206+M2 macrophages inApoe−/−mice treated with pristane. Importantly, pristane inhibited immune cell infiltration into the vascular wall. The upregulation of IL-4 in bone-marrow CD138+plasma cells from pristane-treatedApoe−/−mice was demonstrated by RNA-sequencing (RNA-seq). Consistently, oxidized low-density lipoprotein (oxLDL) directly induced IL-4-secreting plasma cell generation in vitro. In a co-culture system incubating an anti-IL-4 neutralizing antibody, the results showed that oxLDL-induced CD138+plasma cells could boost M2 macrophage polarization via IL-4 secretion. Our data demonstrate an unexpected role that pristane induces IL-4-producing CD138+regulatory plasma cell generation and M2 polarization to protect atherosclerosis development.