Uridine diphosphate drives myeloid differentiation and functional reprogramming through dynamic transcriptional...

Area of Science:

• Immunology
• Cell Biology
• Metabolomics

Background:

• Extracellular nucleotides, including uridine diphosphate (UDP), are key regulators of immune responses via purinergic signaling.
• UDP accumulates in the tumor microenvironment and affects T cell activation, but its impact on human myeloid cells is not well understood.
• Monocytes are crucial precursors for macrophages and dendritic cells, making their response to UDP significant for understanding myeloid cell differentiation.

Purpose of the Study:

• To investigate the effects of uridine diphosphate (UDP) on the proliferation and differentiation potential of human monocytes within peripheral blood mononuclear cells (PBMCs).
• To explore UDP's influence on monocyte-derived dendritic cell (moDC) generation and function, including phagocytosis and efferocytosis.
• To analyze the transcriptomic changes induced by UDP in PBMCs to understand the underlying molecular mechanisms.

Main Methods:

• Peripheral blood mononuclear cells (PBMCs) were stimulated with UDP, and CD14+ monocyte proliferation was assessed using CFSE staining and flow cytometry.
• Dendritic cell differentiation was evaluated in PBMC cultures and purified CD14+ monocytes stimulated with IL-4 and GM-CSF, with or without UDP.
• Phagocytic and efferocytic activities were measured, and transcriptomic profiling was performed using the NanoString Human Immunology Panel.

Main Results:

• UDP significantly suppressed CD14+ monocyte proliferation.
• UDP promoted the differentiation of monocytes into dendritic-like cells (HLA-DR+CD11c+) with enhanced phagocytic and efferocytic capabilities.
• Transcriptomic analysis revealed UDP-driven modulation of inflammatory, antigen-presentation, and regulatory pathways, involving transcription factors like NF-κB and IRF5.

Conclusions:

• Uridine diphosphate (UDP) acts as a potent immunomodulatory metabolite, inhibiting monocyte proliferation while driving differentiation into functionally enhanced dendritic-like cells.
• UDP orchestrates complex transcriptional programs that integrate innate immune activation with adaptive immune regulation.
• These findings highlight UDP's potential role in maintaining immune homeostasis and controlling inflammation through myeloid cell modulation.