Combinatorial processing of bacterial and host-derived innate immune stimuli at the single-cell level
Combinatorial processing of bacterial and host-derived innate immune stimuli at the single-cell level
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DOI：
10.1091/mbc.e18-07-0423
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发表时间：
2019-01-15
影响因子：
3.3
通讯作者：
Covert, Markus W.
中科院分区：
文献类型：
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作者：
Gutschow, Miriam V.;Mason, John C.;Covert, Markus W.
在细菌感染的过程中，细胞同时暴露于一系列细菌和宿主因子，这些因子聚集在中央转录因子核因子(NF)-kappa B上，单个细胞如何整合和处理这些聚集的刺激？在这里，我们解决了细胞如何处理组合信号的问题，方法是对核因子-kappa B对细菌脂多糖和应激细胞因子肿瘤坏死因子组合的反应进行定量的单细胞测量。我们发现，细胞通过单个细胞中核因子-kappa B核转位的动力学来编码这两种刺激的存在，这表明针对这些刺激的核因子-kappa B活性的整合发生在分子和途径水平。然而，基因表达和细胞因子分泌对组合刺激的反应更为复杂，这表明除了核因子-kappa B之外，还有其他因素参与了反应下游层的信号整合。综上所述，我们的结果支持这样的理论，即在先天性免疫威胁评估期间，被认为既是外来的又是有害的病原体会招募增强的免疫反应。我们的工作突出了单个细胞处理多个输入信号的非凡能力，并表明对信号整合机制的深入理解将有助于控制失调的免疫反应。
During the course of a bacterial infection, cells are exposed simultaneously to a range of bacterial and host factors, which converge on the central transcription factor nuclear factor (NF)-kappa B. How do single cells integrate and process these converging stimuli? Here we tackle the question of how cells process combinatorial signals by making quantitative single-cell measurements of the NF-kappa B response to combinations of bacterial lipopolysaccharide and the stress cytokine tumor necrosis factor. We found that cells encode the presence of both stimuli via the dynamics of NF-kappa B nuclear translocation in individual cells, suggesting the integration of NF-kappa B activity for these stimuli occurs at the molecular and pathway level. However, the gene expression and cytokine secretion response to combinatorial stimuli were more complex, suggesting that other factors in addition to NF-kappa B contribute to signal integration at downstream layers of the response. Taken together, our results support the theory that during innate immune threat assessment, a pathogen recognized as both foreign and harmful will recruit an enhanced immune response. Our work highlights the remarkable capacity of individual cells to process multiple input signals and suggests that a deeper understanding of signal integration mechanisms will facilitate efforts to control dysregulated immune responses.