Institute for Quantitative and Computational Biosciences (QCBio), Molecular Biology Institute (MBI), and Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles (UCLA), 611 Charles E. Young Dr S, Los Angeles, CA 90093.
Institute for Quantitative and Computational Biosciences (QCBio), Molecular Biology Institute (MBI), and Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles (UCLA), 611 Charles E. Young Dr S, Los Angeles, CA 90093.
Immunity. 2021 May 11;54(5):916-930.e7. doi: 10.1016/j.immuni.2021.04.011.
Macrophages initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed and thus, the type of response that ensues. Here, we examined how information about the stimulus is encoded in the dynamics of NFκB activity. We generated an mVenus-RelA reporter mouse line to enable high-throughput live-cell analysis of primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features-termed signaling codons-that convey stimulus information to the nucleus. In particular, oscillatory trajectories were a hallmark of responses to cytokine but not pathogen-derived stimuli. Single-cell imaging and RNA sequencing of macrophages from a mouse model of Sjögren's syndrome revealed inappropriate responses to stimuli, suggestive of confusion of two NFκB signaling codons. Thus, the dynamics of NFκB signaling classify immune threats through six signaling codons, and signal confusion based on defective codon deployment may underlie the etiology of some inflammatory diseases.
巨噬细胞通过转录因子 NFκB 引发炎症反应。NFκB 活性的时间模式决定了哪些基因被表达，从而决定了随后发生的反应类型。在这里，我们研究了刺激信息是如何编码在 NFκB 活性的动力学中的。我们生成了一个 mVenus-RelA 报告基因小鼠品系，以实现对原代巨噬细胞响应宿主和病原体来源刺激的高通量活细胞分析。信息论工作流程确定了六个动态特征——称为信号密码子——将刺激信息传递到细胞核。特别是，细胞因子刺激反应的振荡轨迹是其特征，而不是病原体来源刺激的特征。来自干燥综合征小鼠模型的巨噬细胞的单细胞成像和 RNA 测序显示，对刺激的反应不当，提示两种 NFκB 信号密码子混淆。因此，NFκB 信号转导的动力学通过六个信号密码子对免疫威胁进行分类，而基于信号密码子缺陷的信号混淆可能是某些炎症性疾病的病因。
