Transcription factor C/EBPα is required for the development of Ly6Chi monocytes but not Ly6Clo monocytes

• 成果类型: Article
• 署名作者: Kim, Sunkyung; Chen, Jing; Ou, Feiya; Liu, Tian -Tian; Jo, Suin; Gillanders, William E.; Murphy, Theresa L.; Murphy, Kenneth M.
• 署名单位: Washington University (WUSTL)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11879
• DOI: 10.1073/pnas.2315659121
• 发表日期: 2024-04-09
• 关键词: peripheral-blood monocytes; dendritic cells; translational control; ly6c(low) monocytes; myeloid progenitor; macrophages; differentiation; expression; beta; enhancers

摘要

Monocytes comprise two major subsets, Ly6Chi classical monocytes and Ly6Clo nonclassical monocytes. Notch2 signaling in Ly6Chi monocytes triggers transition to Ly6Clo monocytes, which require Nr4a1, Bcl6, Irf2, and Cebpb. By comparison, less is known about transcriptional requirements for Ly6Chi monocytes. We find transcription factor CCAAT/enhancer- binding protein alpha (C/EBP alpha) is highly expressed in Ly6Chi monocytes, but down- regulated in Ly6Clo monocytes. A few previous studies described the requirement of C/EBP alpha in the development of neutrophils and eosinophils. However, the role of C/EBP alpha for in vivo monocyte development has not been understood. We deleted the Cebpa +37 kb enhancer in mice, eliminating hematopoietic expression of C/EBP alpha, reproducing the expected neutrophil defect. Surprisingly, we also found a severe and selective loss of Ly6Chi monocytes, while preserving Ly6Clo monocytes. We find that BM progenitors from Cebpa +37-/- mice rapidly progress through the monocyte progenitor stage to develop directly into Ly6Clo monocytes even in the absence of Notch2 signaling. These results identify a previously unrecognized role for C/EBP alpha in maintaining Ly6Chi monocyte identity. Significance Ly6Clo monocytes, also known as patrolling monocytes, develop from Ly6Chi monocytes and play an important protective role in the surveillance of the vascular endothelium. The development of Ly6Clo monocytes is still incompletely understood. We now demonstrate that the transcription factor CCAAT/ enhancer- binding protein alpha (C/EBP alpha) acts to maintain Ly6Chi monocytes and to repress Ly6Clo monocyte development, adding to our understanding of this protective monocyte subset.