Monocytes differentiate along two alternative pathways during sterile inflammation.

Area of Science:

• Immunology
• Cell Biology
• Transcriptomics

Background:

• Monocytes differentiate into macrophages (mo-Mac) and dendritic cells (mo-DC) in tissues during inflammation.
• The precise differentiation pathways and potential continuum between mo-Mac and mo-DC populations are not fully understood.

Purpose of the Study:

• To investigate whether mo-Mac and mo-DC arise from alternative differentiation pathways or a continuous process.
• To identify key transcription factors governing monocyte fate commitment towards mo-Mac or mo-DC lineages.

Main Methods:

• Temporal single-cell RNA sequencing in an in vitro human monocyte differentiation model.
• In vivo validation using a mouse model of sterile peritonitis.
• Computational analysis to identify candidate transcription factors.

Main Results:

• Monocyte differentiation into mo-Mac and mo-DC follows divergent paths, with a fate decision occurring within 24 hours.
• IRF1 is identified as a crucial transcription factor for mo-Mac differentiation, independent of interferon-stimulated gene regulation.
• ZNF366 and MAFF are identified as key regulators for mo-DC development.

Conclusions:

• Monocyte-derived macrophages and dendritic cells represent distinct cell fates.
• Specific transcription factors, including IRF1, ZNF366, and MAFF, are essential for directing monocyte differentiation into alternative lineages.