title: Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis-infected macrophages.
abstract: Wnt/Frizzled signaling, essential for embryonic development, has also recently been implicated in the modulation of inflammatory processes. In the current study, we observed a reciprocal regulation of the Toll-like receptor (TLR)/nuclear factor-κB (NF-κB) and the Wnt/β-catenin pathway after aerosol infection of mice with Mycobacterium tuberculosis: whereas proinflammatory mediators were substantially increased, β-catenin signaling was significantly reduced. A systematic screen of Fzd homologs in infected mice identified Fzd1 mRNA to be significantly up-regulated during the course of infection. In vitro infection of murine macrophages led to a strong induction of Fzd1 that was dependent on TLRs, the myeloid differentiation response gene 88 (MyD88), and a functional NF-κB pathway. Flow cytometry demonstrated an elevated Fzd1 expression on macrophages in response to M. tuberculosis that was synergistically enhanced in the presence of IFN-γ. Addition of the Fzd1 ligand Wnt3a induced Wnt/β-catenin signaling in murine macrophages that was inhibited in the presence of a soluble Fzd1/Fc fusion protein. Furthermore, Wnt3a reduced TNF release, suggesting that Wnt3a promotes anti-inflammatory functions in murine macrophages. The current data support the notion that evolutionarily conserved Wnt/Fzd signaling is involved in balancing the inflammatory response to microbial stimulation of innate immune cells of vertebrate origin.
authors.affiliation: Division of Microbial Interface Biology, Research Center Borstel, Borstel, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Neumann
authors.forename: Kolja
authors.initials: K
authors.lastname: Schaale
authors.forename: Katja
authors.initials: K
authors.lastname: Farhat
authors.forename: Tobias
authors.initials: T
authors.lastname: Endermann
authors.forename: Artur J
authors.initials: AJ
authors.lastname: Ulmer
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D008024:Ligands; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D015398:Signal Transduction; D014376:Tuberculosis / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000276:immunology; D015854:Up-Regulation; D051153:Wnt Proteins / Q000737:chemistry / Q000276:immunology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D015415:Biomarkers; D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; D008024:Ligands; D016328:NF-kappa B; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D048069:Tumor Necrosis Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse