Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
J Immunol. 2010 May 1;184(9):4810-8. doi: 10.4049/jimmunol.0901368. Epub 2010 Mar 24.
In atherosclerotic arteries, blood monocytes differentiate to macrophages in the presence of growth factors, such as macrophage colony-stimulation factor (M-CSF), and chemokines, such as platelet factor 4 (CXCL4). To compare the gene expression signature of CXCL4-induced macrophages with M-CSF-induced macrophages or macrophages polarized with IFN-gamma/LPS (M1) or IL-4 (M2), we cultured primary human peripheral blood monocytes for 6 d. mRNA expression was measured by Affymetrix gene chips, and differences were analyzed by local pooled error test, profile of complex functionality, and gene set enrichment analysis. Three hundred seventy-five genes were differentially expressed between M-CSF- and CXCL4-induced macrophages; 206 of them overexpressed in CXCL4 macrophages coding for genes implicated in the inflammatory/immune response, Ag processing and presentation, and lipid metabolism. CXCL4-induced macrophages overexpressed some M1 and M2 genes and the corresponding cytokines at the protein level; however, their transcriptome clustered with neither M1 nor M2 transcriptomes. They almost completely lost the ability to phagocytose zymosan beads. Genes linked to atherosclerosis were not consistently upregulated or downregulated. Scavenger receptors showed lower and cholesterol efflux transporters showed higher expression in CXCL4- than M-CSF-induced macrophages, resulting in lower low-density lipoprotein content. We conclude that CXCL4 induces a unique macrophage transcriptome distinct from known macrophage types, defining a new macrophage differentiation that we propose to call M4.
在动脉粥样硬化的血管中，血液单核细胞在生长因子（如巨噬细胞集落刺激因子[M-CSF]）和趋化因子（如血小板因子 4[CXCL4]）的存在下分化为巨噬细胞。为了比较 CXCL4 诱导的巨噬细胞与 M-CSF 诱导的巨噬细胞或用 IFN-γ/LPS（M1）或 IL-4（M2）极化的巨噬细胞的基因表达特征，我们培养了原代人外周血单核细胞 6 天。通过 Affymetrix 基因芯片测量 mRNA 表达，并通过局部汇集误差检验、复杂功能谱和基因集富集分析分析差异。M-CSF 和 CXCL4 诱导的巨噬细胞之间有 375 个基因表达差异；其中 206 个在 CXCL4 巨噬细胞中过表达，编码参与炎症/免疫反应、Ag 处理和呈递以及脂质代谢的基因。CXCL4 诱导的巨噬细胞在蛋白质水平上过度表达一些 M1 和 M2 基因及其相应的细胞因子；然而，它们的转录组与 M1 或 M2 转录组都没有聚类。它们几乎完全丧失了吞噬酵母聚糖珠的能力。与动脉粥样硬化相关的基因没有一致地上调或下调。清道夫受体在 CXCL4 诱导的巨噬细胞中的表达低于 M-CSF 诱导的巨噬细胞，胆固醇流出转运体的表达高于 M-CSF 诱导的巨噬细胞，导致低密度脂蛋白含量降低。我们得出结论，CXCL4 诱导了一种独特的巨噬细胞转录组，与已知的巨噬细胞类型不同，定义了一种新的巨噬细胞分化，我们建议将其称为 M4。
