Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO.
Proc Natl Acad Sci U S A. 2024 Apr 9;121(15):e2315659121. doi: 10.1073/pnas.2315659121. Epub 2024 Apr 2.
Monocytes comprise two major subsets, Ly6C classical monocytes and Ly6C nonclassical monocytes. Notch2 signaling in Ly6C monocytes triggers transition to Ly6C monocytes, which require , , , and . By comparison, less is known about transcriptional requirements for Ly6C monocytes. We find transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is highly expressed in Ly6C monocytes, but down-regulated in Ly6C monocytes. A few previous studies described the requirement of C/EBPα in the development of neutrophils and eosinophils. However, the role of C/EBPα for in vivo monocyte development has not been understood. We deleted the +37 kb enhancer in mice, eliminating hematopoietic expression of C/EBPα, reproducing the expected neutrophil defect. Surprisingly, we also found a severe and selective loss of Ly6C monocytes, while preserving Ly6C monocytes. We find that BM progenitors from +37 mice rapidly progress through the monocyte progenitor stage to develop directly into Ly6C monocytes even in the absence of Notch2 signaling. These results identify a previously unrecognized role for C/EBPα in maintaining Ly6C monocyte identity.
单核细胞分为两大亚群，Ly6C 经典单核细胞和 Ly6C 非经典单核细胞。Ly6C 单核细胞中的 Notch2 信号触发向 Ly6C 单核细胞的转变，该过程需要转录因子 Spi-B、PU.1、IRF8 和 C/EBPα。相比之下，Ly6C 单核细胞的转录要求知之甚少。我们发现转录因子 CCAAT/增强子结合蛋白α（C/EBPα）在 Ly6C 单核细胞中高度表达，但在 Ly6C 单核细胞中下调。先前的一些研究描述了 C/EBPα在中性粒细胞和嗜酸性粒细胞发育中的作用。然而，C/EBPα 在体内单核细胞发育中的作用尚不清楚。我们在小鼠中删除了 +37 kb 增强子，从而消除了 C/EBPα 的造血表达，重现了预期的中性粒细胞缺陷。令人惊讶的是，我们还发现 Ly6C 单核细胞严重且选择性缺失，而 Ly6C 单核细胞则得以保留。我们发现，来自 +37 小鼠的 BM 祖细胞即使在没有 Notch2 信号的情况下，也能迅速通过单核细胞祖细胞阶段，直接发育为 Ly6C 单核细胞。这些结果表明 C/EBPα 在维持 Ly6C 单核细胞特性方面发挥了先前未被认识到的作用。
