Acute and chronic inflammatory pathologies involve misregulation of macrophage functions. Physiologically, macrophages are immune sentinels that initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed, suggesting that a temporal signaling code specifies a stimulus-appropriate immune response. To identify the signaling codewords, we developed tools to enable high-throughput analysis of live, primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features that constitute codewords that convey stimulus information to the nucleus. In particular, oscillatory trajectories are a hallmark of the responses to host cytokine TNF. Remarkably, examining macrophages derived from a systemic autoimmune disease model suggests that confusion of two NFκB signaling codewords, and thus miscoding of TNF as a pathogen-derived stimulus, may underlie sporadic inflammatory pathology. Overall, this study identifies six codewords of the temporal NFκB signaling code for classifying immune threats and demonstrates their biological significance.

中文翻译：

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巨噬细胞用来分类免疫威胁的瞬时NFκB信号码字的鉴定及其生理意义

急性和慢性炎症病理涉及巨噬细胞功能的失调。从生理上讲，巨噬细胞是免疫前哨，可通过转录因子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，这表明时间信号代码指定了一种刺激合适的免疫应答。为了识别信号码字，我们开发了工具，可以对宿主和病原体刺激做出反应，对活的原代巨噬细胞进行高通量分析。信息理论的工作流程确定了六个动态特征，这些特征构成了将刺激信息传递到核的代码字。特别地，振荡轨迹是对宿主细胞因子TNF的响应的标志。值得注意的是 检查源自全身性自身免疫疾病模型的巨噬细胞表明，两个NFκB信号代码字的混淆，以及由此将TNF误编码为病原体衍生的刺激，可能是散发性炎症病理的基础。总体而言，这项研究确定了用于分类免疫威胁的时态NFκB信号代码的六个代码字，并证明了它们的生物学意义。