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

Background Extracellular nucleotides regulate immune responses through purinergic signaling. Uridine diphosphate (UDP), a pyrimidine-derived metabolite, has been shown to accumulate in the tumor microenvironment and modulate T cell activation. However, its effects on human myeloid cells remain poorly understood. Since monocytes represent key precursors for macrophages and dendritic cells, we investigated whether UDP could influence their proliferative and differentiation potential within peripheral blood mononuclear cells (PBMCs). Methods Freshly isolated PBMCs were stimulated with UDP, and CD14 + cell proliferation was analyzed using CFSE staining and flow cytometry. The impact of UDP on dendritic differentiation was evaluated in PBMC cultures and in purified CD14 + monocytes exposed to IL-4 and GM-CSF, in the presence or absence of UDP. Phagocytic and efferocytic activities were assessed using fluorescently labeled E. coli and apoptotic HeLa cells, respectively. Transcriptomic profiling of PBMCs stimulated with UDP for 2, 6, or 24 hours was performed using the NanoString Human Immunology Panel. Results UDP markedly suppressed CD14 + monocyte proliferation and promoted the generation of HLA-DR + CD11c + dendritic-like cells. In purified monocytes, UDP enhanced IL-4/GM-CSF-driven differentiation into CD14 - CD16 - HLA-DR + CD11c + monocyte-derived dendritic cells (moDCs). Functionally, UDP increased both bacterial phagocytosis and efferocytosis. Transcriptomic analysis revealed eight gene clusters with distinct temporal expression patterns, driven by transcription factors such as NF-κB, RUNX3, BATF, and IRF5, indicating coordinated modulation of inflammatory, antigen-presentation, and regulatory pathways. Conclusion Our findings identify UDP as a potent immunomodulatory metabolite that restricts monocyte proliferation while promoting differentiation into dendritic-like cells with enhanced phagocytic capacity. UDP engages complex transcriptional programs that integrate innate activation with adaptive immune regulation, highlighting its potential role in immune homeostasis and inflammation control.