Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Atherosclerosis. 2011 Feb;214(2):345-9. doi: 10.1016/j.atherosclerosis.2010.11.018. Epub 2010 Nov 27.
Macrophages are key players in atherogenesis because of their properties to form foam cells that produce a large variety of pro-inflammatory mediators. We addressed the potency of phenotypic different macrophages to accumulate oxidized LDL.
Surprisingly, anti-inflammatory M2 macrophages but not pro-inflammatory M1 macrophages rapidly accumulated oxidized LDL. Simultaneously, expression of Krüppel-like factor 2, a nuclear transcription factor known to suppress inflammation in endothelial cells and monocytes, decreased and the functional phenotype of M2 macrophages shifted towards a pro-inflammatory profile, characterized by higher production of IL-6, IL-8 and MCP-1 and lower expression of IL-10 upon stimulation with LPS. In contrast, Krüppel-like factor 2 expression and the phenotype of M1 macrophages remained largely unchanged upon oxidized LDL exposure. Downregulation of Krüppel-like factor 2 expression of M2 macrophages using siRNA technology led to a significant increase of LPS-induced MCP-1 secretion.
We show that (1) anti-inflammatory M2 macrophages are more susceptible to foam cell formation than pro-inflammatory M1 macrophages, (2) exposure to oxidized LDL renders M2 macrophages pro-inflammatory, and (3) Krüppel-like factor 2 is involved in the enhanced secretion of MCP-1 by M2 macrophages loaded with oxidized LDL. The phenotype switch of M2 macrophages from an anti- to a pro-inflammatory profile may play an important role in pathogenesis of atherosclerosis, and could represent a novel therapeutic target.
巨噬细胞是动脉粥样硬化形成的关键因素，因为它们能够形成泡沫细胞，产生多种促炎介质。我们研究了表型不同的巨噬细胞摄取氧化型 LDL 的能力。
令人惊讶的是，抗炎型 M2 巨噬细胞而非促炎型 M1 巨噬细胞能迅速摄取氧化型 LDL。同时，核转录因子 Krüppel 样因子 2 的表达（已知可抑制内皮细胞和单核细胞中的炎症）下降，M2 巨噬细胞的功能表型向促炎型转变，其特征是 LPS 刺激后 IL-6、IL-8 和 MCP-1 的产生增加，而 IL-10 的表达降低。相比之下，M1 巨噬细胞在暴露于氧化型 LDL 后，Krüppel 样因子 2 的表达和表型基本保持不变。用 siRNA 技术下调 M2 巨噬细胞中 Krüppel 样因子 2 的表达，导致 LPS 诱导的 MCP-1 分泌显著增加。
我们表明（1）抗炎型 M2 巨噬细胞比促炎型 M1 巨噬细胞更容易形成泡沫细胞，（2）氧化型 LDL 使 M2 巨噬细胞呈现促炎状态，（3）Krüppel 样因子 2 参与了负载氧化型 LDL 的 M2 巨噬细胞中 MCP-1 的分泌增加。M2 巨噬细胞从抗炎型向促炎型表型的表型转换可能在动脉粥样硬化的发病机制中起重要作用，并可能成为一个新的治疗靶点。
