Department of Microbiology, Immunology, and Molecular Genetics, and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, 611 Charles E. Young Dr S, Los Angeles, CA 90093, USA.
Department of Microbiology, Immunology, and Molecular Genetics, and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, 611 Charles E. Young Dr S, Los Angeles, CA 90093, USA.
Cell Syst. 2023 Mar 15;14(3):180-195.e5. doi: 10.1016/j.cels.2022.12.012. Epub 2023 Jan 18.
Immune sentinel macrophages initiate responses to pathogens via hundreds of immune response genes. Each immune threat demands a tailored response, suggesting that the capacity for stimulus-specific gene expression is a key functional hallmark of healthy macrophages. To quantify this property, termed "stimulus-response specificity" (SRS), we developed a single-cell experimental workflow and analytical approaches based on information theory and machine learning. We found that the response specificity of macrophages is driven by combinations of specific immune genes that show low cell-to-cell heterogeneity and are targets of separate signaling pathways. The "response specificity profile," a systematic comparison of multiple stimulus-response distributions, was distinctly altered by polarizing cytokines, and it enabled an assessment of the functional state of macrophages. Indeed, the response specificity profile of peritoneal macrophages from old and obese mice showed characteristic differences, suggesting that SRS may be a basis for measuring the functional state of innate immune cells. A record of this paper's transparent peer review process is included in the supplemental information.
免疫哨兵巨噬细胞通过数百个免疫反应基因启动对病原体的反应。每种免疫威胁都需要量身定制的反应，这表明刺激特异性基因表达的能力是健康巨噬细胞的一个关键功能标志。为了量化这种特性，称为“刺激-反应特异性”（SRS），我们开发了一种基于信息论和机器学习的单细胞实验工作流程和分析方法。我们发现，巨噬细胞的反应特异性是由表现出低细胞间异质性且是独立信号通路靶标的特定免疫基因组合驱动的。“反应特异性谱”是对多个刺激-反应分布的系统比较，被极化细胞因子明显改变，并能够评估巨噬细胞的功能状态。事实上，来自年老和肥胖小鼠的腹腔巨噬细胞的反应特异性谱表现出特征性差异，表明 SRS 可能是衡量固有免疫细胞功能状态的基础。本论文的透明同行评审过程记录包含在补充信息中。
