Quantifying dynamic pro-inflammatory gene expression and heterogeneity in single macrophage cells.
Quantifying dynamic pro-inflammatory gene expression and heterogeneity in single macrophage cells.
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量化单个巨噬细胞中的动态促炎基因表达和异质性。
DOI：
10.1016/j.jbc.2023.105230
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发表时间：
2023-10
期刊：
影响因子：
0.8
通讯作者：
Hao, Nan
中科院分区：
文献类型：
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作者：
Naigles, Beverly;Soroczynski, Jan;Hao, Nan
巨噬细胞必须对病原体和其他促炎刺激做出适当反应，以发挥其在对抗感染中的作用。炎症刺激的一种变化方式是它们的动力学，即细胞所经历的刺激的幅度和持续时间。在这项研究中，我们在微流控装置中进行了长期活细胞成像，以研究促炎基因IRF1，CXCL10和CXCL9如何响应动态干扰素γ（IFNγ）刺激。我们发现IRF 1对低浓度或短时间的IFNγ刺激有反应，而CXCL 10和CXCL 9需要更长或更高浓度的刺激才能表达。我们还研究了每个基因表达的异质性，发现CXCL10和CXCL9具有显著的细胞间变异性。特别是，CXCL10的表达似乎在很大程度上是随机的，在所有测试的刺激条件下都有一个无反应细胞亚群。我们为每个基因的表达开发了确定性和随机性模型。我们的建模分析表明，CXCL10的异质性可以归因于一个缓慢的染色质开放步骤，这是一个类似的时间尺度上的上游信号的适应。通过这种方式，单个细胞中的CXCL10表达可以响应于重复刺激的每个脉冲而保持随机性，我们也通过实验验证了这一点。总之，我们得出结论，在同一信号通路中的促炎基因可以响应动态IFNγ刺激，具有非常不同的响应特征，上游信号适应可以有助于形成异质性基因表达。
Macrophages must respond appropriately to pathogens and other pro-inflammatory stimuli in order to perform their roles in fighting infection. One way in which inflammatory stimuli can vary is in their dynamics—that is, the amplitude and duration of stimulus experienced by the cell. In this study, we performed long-term live cell imaging in a microfluidic device to investigate how the pro-inflammatory genes IRF1, CXCL10, and CXCL9 respond to dynamic interferon-gamma (IFNγ) stimulation. We found that IRF1 responds to low concentration or short duration IFNγ stimulation, whereas CXCL10 and CXCL9 require longer or higherconcentration stimulation to be expressed. We also investigated the heterogeneity in the expression of each gene and found that CXCL10 and CXCL9 have substantial cell-to-cell variability. In particular, the expression of CXCL10 appears to be largely stochastic with a subpopulation of nonresponding cells across all the stimulation conditions tested. We developed both deterministic and stochastic models for the expression of each gene. Our modeling analysis revealed that the heterogeneity in CXCL10 can be attributed to a slow chromatin-opening step that is on a similar timescale to that of adaptation of the upstream signal. In this way, CXCL10 expression in individual cells can remain stochastic in response to each pulse of repeated stimulation, which we also validated by experiments. Together, we conclude that pro-inflammatory genes in the same signaling pathway can respond to dynamic IFNγ stimulus with very different response features and that upstream signal adaptation can contribute to shaping heterogeneous gene expression.
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