Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
Department of Immunology, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2021 Jan 12;12(1):301. doi: 10.1038/s41467-020-20540-2.
Macrophages are innate immune cells that contribute to fighting infections, tissue repair, and maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve potentially conflicting cues in the microenvironment via mechanisms that are unclear. Here, we use single-cell RNA sequencing to explore how individual macrophages respond when co-stimulated with inflammatory stimuli LPS and IFN-γ and the resolving cytokine IL-4. These co-stimulated macrophages display a distinct global transcriptional program. However, variable negative cross-regulation between some LPS + IFN-γ-specific and IL-4-specific genes results in cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation leads to mutually exclusive expression of the T-cell-polarizing cytokine genes Il6 and Il12b versus the IL-4-associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion measurements show that these specialized functions are maintained for at least 48 h. This study suggests that increasing functional diversity in the population is one strategy macrophages use to respond to conflicting environmental cues.
巨噬细胞是先天免疫细胞，有助于抵抗感染、组织修复和维持组织内稳态。为了实现这种功能多样性，巨噬细胞通过尚不清楚的机制来解决微环境中潜在的冲突信号。在这里，我们使用单细胞 RNA 测序来探索当单个巨噬细胞受到炎症刺激物 LPS 和 IFN-γ 以及具有抗炎作用的细胞因子 IL-4 的共同刺激时会如何反应。这些共同刺激的巨噬细胞显示出明显的全局转录程序。然而，一些 LPS+IFN-γ 特异性和 IL-4 特异性基因之间的可变负交叉调节导致转录的细胞间异质性。有趣的是，负交叉调节导致在单个共刺激巨噬细胞中 T 细胞极化细胞因子基因 Il6 和 Il12b 与 IL-4 相关因子 Arg1 和 Chil3 的表达相互排斥，单细胞分泌测量表明这些特化功能至少维持 48 小时。这项研究表明，增加群体中的功能多样性是巨噬细胞用来应对环境信号冲突的一种策略。
