Wnt5a inhibits human monocyte-derived myeloid dendritic cell generation.

Wnt5a is a non-canonical Wnt protein that is expressed at elevated levels in inflammatory conditions. Its role in inflammation remains unclear, although it is known that Wnt5a is expressed at a higher level in monocyte-derived myeloid dendritic cells (Mo-mDCs) than in monocytes and macrophages. The function of Wnt5a in dendritic cells (DCs) remains relatively unexplored. Here, we found that under Mo-mDC culture conditions, Wnt5a inhibited the generation of CD14(⁺/low) Mo-mDCs while promoting the generation of CD14⁺/⁺⁺ CD16⁺ monocytes. We could further show that stimulation of monocytes with rWnt5a induced a rapid IL-6 production and that the rWnt5a treated Mo-mDC differentiation was restored upon blocking of IL-6. Also, conditioned media from Wnt5a stimulated human breast cancer cells producing IL-6, specifically inhibited Mo-mDC differentiation. These observations are strengthened by our finding that patients with sepsis, a disease involving elevated Wnt5a and IL-6 levels, also showed a significant increase in the CD14⁺ CD16⁺⁺/CD14⁺/⁺⁺ CD16⁺ monocyte populations, which was accompanied by a significant decrease in circulating mDCs. We finally show that under typical Mo-mDC culture conditions, monocytes isolated from patients with sepsis as compared to healthy controls, preferentially differentiated into CD14CD14⁺/⁺⁺ HLA-DR⁺⁺ cells. We suggest that Wnt5a is a possible candidate mediator for the CD14⁺/⁺⁺ CD16⁺ monocyte accumulation seen in patients with infectious disease and cancer.