氧化型低密度脂蛋白通过激活 CD36 清道夫受体使嗜酸性粒细胞极化为 M1 型巨噬细胞表型。
Oxidized LDL activated eosinophil polarize macrophage phenotype from M2 to M1 through activation of CD36 scavenger receptor.
机构信息
Oppenheimer Atherosclerosis Research Center, Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
出版信息
Atherosclerosis. 2017 Aug;263:82-91. doi: 10.1016/j.atherosclerosis.2017.05.011. Epub 2017 May 20.
BACKGROUND AND AIMS
Inflammation, particularly innate immunity, plays an important role in cardiovascular diseases. The aim of this study was to investigate whether atherogenic determinants such as oxidized LDL modulate the phenotype of eosinophils.
METHODS
Cultured eosinophils were treated with oxidized LDL and the expression of selective inflammatory and anti-inflammatory cytokines was determined. In addition, the eosinophil receptor and signaling that mediate these events were identified.
RESULTS
Treatment of cultured eosinophils with oxidized LDL (Ox-LDL) specifically induced the expression of IFNα and IFNβ without affecting expression of other proinflammatory cytokines, such as TNFα, IL-1β, and IL-6. In macrophages, Ox-LDL downregulated expression of both IFNα and IFNβ, suggesting that the effect of Ox-LDL on the expression of type I interferons is specific to eosinophils. Furthermore, we noted that eosinophils constitutively expressed IL-4 and IL-13, and Ox-LDL markedly downregulated their expression. Analysis of Ox-LDL signaling revealed that eosinophils constitutively expressed SRB2, CD36, and CD68 scavenger receptors, and Ox-LDL markedly induced the expression of CD36. Further analysis of CD36 signaling by siRNA and neutralizing antibodies showed that the induction of type I IFN by Ox-LDL is mediated by CD36 signaling whereas downregulation of IL-4 is independent of CD36 activation. We further showed that peritoneal macrophages treated with condition medium collected from Ox-LDL treated eosinophils markedly induced the expression of M1 markers such as iNOS, IL6, SOSC3 and TNFα whereas the condition medium from non-treated eosinophils significantly induced expression of M2 markers like ARG1 and CCL24.
CONCLUSIONS
Our data suggest that an atherogenic condition could activate eosinophils and modulate the phenotype of macrophages (from M2 to M1 phenotype), in part, through the CD36 receptor signaling.
背景与目的
炎症，特别是先天免疫，在心血管疾病中起着重要作用。本研究旨在探讨动脉粥样硬化决定因素（如氧化 LDL）是否调节嗜酸性粒细胞的表型。
方法
用氧化 LDL 处理培养的嗜酸性粒细胞，测定选择性炎症和抗炎细胞因子的表达。此外，还鉴定了介导这些事件的嗜酸性粒细胞受体和信号转导。
结果
用氧化 LDL（Ox-LDL）处理培养的嗜酸性粒细胞可特异性诱导 IFNα 和 IFNβ 的表达，而不影响 TNFα、IL-1β 和 IL-6 等其他促炎细胞因子的表达。在巨噬细胞中，Ox-LDL 下调了 IFNα 和 IFNβ 的表达，这表明 Ox-LDL 对 I 型干扰素表达的影响是嗜酸性粒细胞特异性的。此外，我们注意到嗜酸性粒细胞固有地表达 IL-4 和 IL-13，而 Ox-LDL 明显下调其表达。Ox-LDL 信号转导分析表明，嗜酸性粒细胞固有地表达 SRB2、CD36 和 CD68 清道夫受体，而 Ox-LDL 明显诱导 CD36 的表达。用 siRNA 和中和抗体进一步分析 CD36 信号转导表明，Ox-LDL 诱导 I 型 IFN 的表达是通过 CD36 信号转导介导的，而 IL-4 的下调与 CD36 激活无关。我们进一步表明，用 Ox-LDL 处理的嗜酸性粒细胞条件培养基处理的腹腔巨噬细胞明显诱导了 iNOS、IL6、SOCS3 和 TNFα 等 M1 标志物的表达，而未经处理的嗜酸性粒细胞的条件培养基则显著诱导了 ARG1 和 CCL24 等 M2 标志物的表达。
结论
我们的数据表明，动脉粥样硬化条件可以激活嗜酸性粒细胞，并通过 CD36 受体信号转导部分调节巨噬细胞的表型（从 M2 表型到 M1 表型）。
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