title: Wnt5a skews dendritic cell differentiation to an unconventional phenotype with tolerogenic features.
abstract: Dendritic cells (DCs) are critical regulators of immune responses that integrate signals from the innate and adaptive immune system and orchestrate T cell responses toward either immunity or tolerance. Growing evidence points to the Wnt signaling pathway as a pivotal piece in the immune balance and focuses on DCs as a direct target for their immunoregulatory role. Our results show that the increase in Wnt5a signaling during the differentiation of human DCs from monocytes alters their phenotype and compromises their subsequent capacity to mature in response to TLR-dependent stimuli. These Wnt5a-DCs produce scant amounts of IL-12p70 and TNF-α but increased levels of IL-10. Consequently, these Wnt5a-DCs have a reduced capacity to induce Th1 responses that promote IL-10 secretion by CD4 T cells. Changes in the transcriptional profile of Wnt5a-DCs correlate with their unconventional phenotype caused presumably by increased IL-6/IL-10 signaling during the process of DC differentiation. The effect of Wnt5a is not a consequence of β-catenin accumulation but is dependent on noncanonical Ca(2+)/calmodulin-dependent protein kinase II/NF-κB signaling. Our results therefore suggest that under high levels of Wnt5a, typical of the inflammatory state and sepsis, monocytes could differentiate into unconventional DCs with tolerogenic features.
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
authors.forename: Jaris
authors.initials: J
authors.lastname: Valencia
authors.forename: Carmen
authors.initials: C
authors.lastname: Hernández-López
authors.forename: Víctor G
authors.initials: VG
authors.lastname: Martínez
authors.forename: Laura
authors.initials: L
authors.lastname: Hidalgo
authors.forename: Agustín G
authors.initials: AG
authors.lastname: Zapata
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Vicente
authors.forename: Alberto
authors.initials: A
authors.lastname: Varas
authors.forename: Rosa
authors.initials: R
authors.lastname: Sacedón
mesh_terms: D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051153:Wnt Proteins / Q000276:immunology* / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein