Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Circ Res. 2010 Sep 17;107(6):737-46. doi: 10.1161/CIRCRESAHA.109.215715. Epub 2010 Jul 22.
Macrophages change their phenotype and biological functions depending on the microenvironment. In atherosclerosis, oxidative tissue damage accompanies chronic inflammation; however, macrophage phenotypic changes in response to oxidatively modified molecules are not known.
To examine macrophage phenotypic changes in response to oxidized phospholipids that are present in atherosclerotic lesions.
We show that oxidized phospholipid-treated murine macrophages develop into a novel phenotype (Mox) that is strikingly different from the conventional M1 and M2 macrophage phenotypes. Compared to M1 and M2, Mox macrophages show a different gene expression pattern, as well as decreased phagocytotic and chemotactic capacity. Treatment with oxidized phospholipids induces both M1 and M2 macrophages to switch to the Mox phenotype. Whole-genome expression array analysis and subsequent gene ontology clustering revealed that the Mox phenotype was characterized by abundant overrepresentation of Nrf2-mediated expression of redox-regulatory genes. In macrophages isolated from Nrf2(-/-) mice, oxidized phospholipid-induced gene expression and regulation of redox status were compromised. Moreover, we found that Mox macrophages comprise 30% of all macrophages in advanced atherosclerotic lesions of low-density lipoprotein receptor knockout (LDLR(-/-)) mice.
Together, we identify Nrf2 as a key regulator in the formation of a novel macrophage phenotype (Mox) that develops in response to oxidative tissue damage. The unique biological properties of Mox macrophages suggest this phenotype may play an important role in atherosclerotic lesion development as well as in other settings of chronic inflammation.
巨噬细胞根据微环境改变其表型和生物学功能。在动脉粥样硬化中，氧化组织损伤伴随着慢性炎症；然而，对于氧化修饰分子引起的巨噬细胞表型变化尚不清楚。
研究氧化磷脂在动脉粥样硬化病变中存在时对巨噬细胞表型的变化。
我们表明，氧化磷脂处理的鼠巨噬细胞发育成一种新型表型（Mox），与传统的 M1 和 M2 巨噬细胞表型明显不同。与 M1 和 M2 相比，Mox 巨噬细胞表现出不同的基因表达模式，以及吞噬和趋化能力降低。氧化磷脂处理诱导 M1 和 M2 巨噬细胞向 Mox 表型转变。全基因组表达谱分析和随后的基因本体聚类表明，Mox 表型的特征是 Nrf2 介导的氧化还原调节基因表达的丰富过度表达。在 Nrf2(-/-) 小鼠分离的巨噬细胞中，氧化磷脂诱导的基因表达和氧化还原状态的调节受损。此外，我们发现 Mox 巨噬细胞占低密度脂蛋白受体敲除（LDLR(-/-)）小鼠晚期动脉粥样硬化病变中所有巨噬细胞的 30%。
总之，我们确定 Nrf2 是一种关键调节剂，可形成一种新型巨噬细胞表型（Mox），该表型在氧化组织损伤时发展。Mox 巨噬细胞的独特生物学特性表明，这种表型可能在动脉粥样硬化病变发展以及其他慢性炎症环境中发挥重要作用。
