Department of Biochemistry and Molecular Biology, Faculty of Medicine.
Doctoral School of Molecular Cell and Immune Biology; and.
JCI Insight. 2024 Sep 10;9(17):e164009. doi: 10.1172/jci.insight.164009.
Alveolar macrophages (AMs) act as gatekeepers of the lung's immune responses, serving essential roles in recognizing and eliminating pathogens. The transcription factor (TF) early growth response 2 (EGR2) has been recently described as required for mature AMs in mice; however, its mechanisms of action have not been explored. Here, we identified EGR2 as an epigenomic regulator and likely direct proximal transcriptional activator in AMs using epigenomic approaches (RNA sequencing, ATAC sequencing, and CUT&RUN). The predicted direct proximal targets of EGR2 included a subset of AM identity genes and ones related to pathogen recognition, phagosome maturation, and adhesion, such as Clec7a, Atp6v0d2, Itgb2, Rhoc, and Tmsb10. We provided evidence that EGR2 deficiency led to impaired zymosan internalization and reduced the capacity to respond to Aspergillus fumigatus. Mechanistically, the lack of EGR2 altered the transcriptional response, secreted cytokines (i.e., CXCL11), and inflammation-resolving lipid mediators (i.e., RvE1) of AMs during in vivo zymosan-induced inflammation, which manifested in impaired resolution. Our findings demonstrated that EGR2 is a key proximal transcriptional activator and epigenomic bookmark in AMs responsible for select, distinct components of cell identity and a protective transcriptional and epigenomic program against fungi.
肺泡巨噬细胞（AMs）作为肺部免疫反应的守门员，在识别和清除病原体方面发挥着重要作用。转录因子（TF）早期生长反应 2（EGR2）最近被描述为小鼠成熟 AM 所必需的；然而，其作用机制尚未得到探索。在这里，我们使用表观基因组学方法（RNA 测序、ATAC 测序和 CUT&RUN）鉴定 EGR2 作为 AMs 中的表观基因组调节剂和可能的直接近端转录激活剂。EGR2 的预测直接近端靶标包括 AM 身份基因的子集和与病原体识别、吞噬体成熟和黏附相关的基因，如 Clec7a、Atp6v0d2、Itgb2、Rhoc 和 Tmsb10。我们提供的证据表明，EGR2 缺乏导致酵母聚糖内化受损，并且对烟曲霉的反应能力降低。在机制上，缺乏 EGR2 改变了 AMs 在体内酵母聚糖诱导的炎症过程中的转录反应、分泌细胞因子（即 CXCL11）和炎症消退脂质介质（即 RvE1），表现为消退受损。我们的研究结果表明，EGR2 是 AMs 中负责选择、独特细胞身份成分的关键近端转录激活剂和表观基因组书签，以及针对真菌的保护性转录和表观基因组程序。
