title: Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients.
abstract: A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.
authors.affiliation: Center for Molecular Pathology, Skåne University Hospital, Lund University, 20502 Malmö, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bergenfelz
authors.forename: Catharina
authors.initials: C
authors.lastname: Medrek
authors.forename: Elin
authors.initials: E
authors.lastname: Ekström
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Helena
authors.initials: H
authors.lastname: Janols
authors.forename: Marlene
authors.initials: M
authors.lastname: Wullt
authors.forename: Anders
authors.initials: A
authors.lastname: Bredberg
authors.forename: Karin
authors.initials: K
authors.lastname: Leandersson
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051153:Wnt Proteins / Q000502:physiology*; D000071818:Wnt-5a Protein
chemical_list: D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein