Model-Based Characterization of Inflammatory Gene Expression Patterns of Activated Macrophages
Model-Based Characterization of Inflammatory Gene Expression Patterns of Activated Macrophages
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DOI：
10.1371/journal.pcbi.1005018
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发表时间：
2016-07-01
影响因子：
4.3
通讯作者：
Bode, Johannes G.
中科院分区：
文献类型：
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作者：
Rex, Julia;Albrecht, Ute;Bode, Johannes G.
巨噬细胞是具有显著可塑性的细胞。它们将来自微环境的信号整合到经典（M1）或替代（M2）激活的巨噬细胞中，代表了广泛的不同表型的两个极端。因此，巨噬细胞向受损组织传递保护和促再生信号，但根据引起的损伤，也可能导致组织损伤的产生和加重。尽管尚未完全理解，但有新的证据表明巨噬细胞极化对这些拮抗作用至关重要。为了确定可能赋予这些不同作用的趋化因子和细胞因子的激活特异性表达模式，应用了系统生物学方法。建立了基于文献的综合布尔模型来描述M1 （lps激活）和M2 （il -4/13激活）极化类型。利用小鼠骨髓源性巨噬细胞的高通量转录物表达数据验证了该模型。通过基因表达的动态建模，估计了途径激活和自分泌信号的时序。我们的研究结果加深了对导致M1/M2激活的生理平衡的理解，表明Akt1或Akt2水平上的共调节信号的相关性可能对指导巨噬细胞极化很重要。
Macrophages are cells with remarkable plasticity. They integrate signals from their microenvironment leading to context-dependent polarization into classically (M1) or alternatively (M2) activated macrophages, representing two extremes of a broad spectrum of divergent phenotypes. Thereby, macrophages deliver protective and pro-regenerative signals towards injured tissue but, depending on the eliciting damage, may also be responsible for the generation and aggravation of tissue injury. Although incompletely understood, there is emerging evidence that macrophage polarization is critical for these antagonistic roles. To identify activation-specific expression patterns of chemokines and cytokines that may confer these distinct effects a systems biology approach was applied. A comprehensive literature-based Boolean model was developed to describe the M1 (LPS-activated) and M2 (IL-4/13-activated) polarization types. The model was validated using high-throughput transcript expression data from murine bone marrow derived macrophages. By dynamic modeling of gene expression, the chronology of pathway activation and autocrine signaling was estimated. Our results provide a deepened understanding of the physiological balance leading to M1/M2 activation, indicating the relevance of co-regulatory signals at the level of Akt1 or Akt2 that may be important for directing macrophage polarization.