经历 M1 型与 M2 型极化的巨噬细胞在细胞代谢和细胞功能方面存在显着差异。在这里，全局定量时程蛋白质组学和磷酸蛋白质组学与转录组学相结合，提供了 M1 型与 M2 型极化诱导阶段发生的细胞代谢、细胞功能和信号通路的时间变化的全面表征。特别是在代谢途径方面观察到显着差异，包括葡萄糖代谢、糖胺聚糖代谢和视黄酸信号传导的变化。激酶富集分析显示了 M1 型与 M2 型极化中不同的特定激酶的激活模式。 M2 型极化抑制剂药物筛选可识别选择性阻断 M2 型极化而非 M1 型极化的药物，包括丝裂原激活蛋白激酶激酶 (MEK) 和组蛋白脱乙酰酶 (HDAC) 抑制剂。这些数据集提供了全面的资源来识别对巨噬细胞极化至关重要的特定信号传导和代谢途径。在原理验证方法中，我们使用这些数据集来证明 MEK 信号传导是通过促进过氧化物酶体增殖物激活受体-γ (PPARγ) 诱导的视黄酸信号传导来实现 M2 型极化所必需的。
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Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors
Macrophages undergoing M1- versus M2-type polarization differ significantly in their cell metabolism and cellular functions. Here, global quantitative time-course proteomics and phosphoproteomics paired with transcriptomics provide a comprehensive characterization of temporal changes in cell metabolism, cellular functions, and signaling pathways that occur during the induction phase of M1- versus M2-type polarization. Significant differences in, especially, metabolic pathways are observed, including changes in glucose metabolism, glycosaminoglycan metabolism, and retinoic acid signaling. Kinase-enrichment analysis shows activation patterns of specific kinases that are distinct in M1- versus M2-type polarization. M2-type polarization inhibitor drug screens identify drugs that selectively block M2- but not M1-type polarization, including mitogen-activated protein kinase kinase (MEK) and histone deacetylase (HDAC) inhibitors. These datasets provide a comprehensive resource to identify specific signaling and metabolic pathways that are critical for macrophage polarization. In a proof-of-principle approach, we use these datasets to show that MEK signaling is required for M2-type polarization by promoting peroxisome proliferator-activated receptor-γ (PPARγ)-induced retinoic acid signaling.