title: Wnt5a inhibits human monocyte-derived myeloid dendritic cell generation.
abstract: 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.
authors.affiliation: Center for Molecular Pathology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Bergenfelz
authors.forename: H
authors.initials: H
authors.lastname: Janols
authors.forename: M
authors.initials: M
authors.lastname: Wullt
authors.forename: K
authors.initials: K
authors.lastname: Jirström
authors.forename: A
authors.initials: A
authors.lastname: Bredberg
authors.forename: K
authors.initials: K
authors.lastname: Leandersson
mesh_terms: D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D000071818:Wnt-5a Protein; D000093242:Interleukin-6 Inhibitors
chemical_list: D017077:Culture Media, Conditioned; D006684:HLA-DR Antigens; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D011994:Recombinant Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C085389:WNT5A protein, human