Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses.
Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses.
复制标题
DOI：
10.1016/j.immuni.2021.04.011
复制
发表时间：
2021-05-11
期刊：
影响因子：
32.4
通讯作者：
Hoffmann A
中科院分区：
文献类型：
--
作者：
Adelaja A;Taylor B;Sheu KM;Liu Y;Luecke S;Hoffmann A
巨噬细胞通过转录因子NFκB启动炎症反应。NFκB活性的时间模式决定了哪些基因被表达，从而决定了引发的反应类型。在这里，我们研究了有关刺激的信息是如何在NFκB活性的动力学中编码的。我们产生了mVenus-RelA报告基因小鼠系，以实现对宿主和病原体来源的刺激作出反应的原代巨噬细胞的高通量活细胞分析。一个信息理论的工作流程确定了六个动态功能-称为信号密码子-将刺激信息传递到细胞核。特别是，振荡轨迹是对细胞因子而不是病原体来源的刺激的反应的标志。干燥综合征小鼠模型巨噬细胞的单细胞成像和RNA测序显示对刺激的不适当反应，提示两个NFκB信号密码子的混淆。因此，NFκB信号传导的动力学通过六个信号传导密码子对免疫威胁进行分类，并且基于缺陷密码子部署的信号混淆可能是某些炎性疾病的病因学基础。Adelaja和Taylor等人使用RelA-mVenus报告小鼠在单细胞水平上检查了响应不同刺激的原代巨噬细胞中NFκB活化动力学。他们的发现定义了六个动态特征-信号密码子-对免疫威胁进行分类，并进一步表明信号“混乱”可能有助于自身免疫病理学。
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. Adelaja and Taylor et al. use a RelA-mVenus reporter mouse to examine, at single-cell level, the NFκB activation dynamics in primary macrophages responding to different stimuli. Their findings define six dynamical features—signaling codons—that classify immune threats and further suggest that signal “confusion” may contribute to autoimmune pathology.
登录
查看更多内容
影响因子：
9.3
作者：
Cheng CS;Behar MS;Suryawanshi GW;Feldman KE;Spreafico R;Hoffmann A
通讯作者：
Hoffmann A
影响因子：
4
作者：
Behar, Marcelo;Hoffmann, Alexander
通讯作者：
Hoffmann, Alexander
影响因子：
6.5
作者：
Bauer, J;Bahmer, FA;Fartasch, M
通讯作者：
Fartasch, M
影响因子：
3.3
作者：
Gutschow, Miriam V.;Mason, John C.;Covert, Markus W.
通讯作者：
Covert, Markus W.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK