Abstract
The Wnt signaling network, an ancient signaling system governing ontogeny and homeostatic processes, has recently been identified to exert immunoregulatory functions in a variety of inflammatory and infectious disease settings including tuberculosis. In this study, we show that Wnt6 is expressed in granulomatous lesions in the lung of Mycobacterium tuberculosis-infected mice. We identified foamy macrophage-like cells as the primary source of Wnt6 in the infected lung and uncovered a TLR-MyD88-NF-κB-dependent mode of induction in bone marrow-derived macrophages. Analysis of Wnt6-induced signal transduction revealed a pertussis toxin-sensitive, ERK-mediated, but β-catenin-independent induction of c-Myc, a master regulator of cell proliferation. Increased Ki-67 mRNA expression levels and enhanced thymidine incorporation in Wnt6-treated macrophage cultures demonstrate a proliferation-promoting effect on murine macrophages. Further functional studies in M. tuberculosis-infected macrophages using Wnt6 conditioned medium and Wnt6-deficient macrophages uncovered a Wnt6-dependent induction of macrophage Arginase-1 and downregulation of TNF-α. This identifies Wnt6 as a novel factor driving macrophage polarization toward an M2-like phenotype. Taken together, these findings point to an unexpected role for Wnt6 in macrophage differentiation in the M. tuberculosis-infected lung.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arginase / biosynthesis
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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Cell Differentiation / immunology
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Cell Proliferation
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Culture Media, Conditioned / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Granuloma / metabolism
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Ki-67 Antigen / biosynthesis
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Ki-67 Antigen / genetics
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Lung / metabolism
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Lung / microbiology
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Lung / pathology
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mycobacterium tuberculosis / immunology
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism*
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NF-kappa B / metabolism*
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Pertussis Toxin / metabolism
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Messenger / biosynthesis
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism*
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Tuberculosis, Pulmonary / immunology
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Tuberculosis, Pulmonary / metabolism*
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Tumor Necrosis Factor-alpha / genetics
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Wnt Proteins / biosynthesis
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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Wnt Signaling Pathway / immunology
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beta Catenin / metabolism
Substances
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Culture Media, Conditioned
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Ki-67 Antigen
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Mki67 protein, mouse
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Myc protein, mouse
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Tumor Necrosis Factor-alpha
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Wnt Proteins
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Wnt6 protein, mouse
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beta Catenin
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Pertussis Toxin
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Extracellular Signal-Regulated MAP Kinases
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Arg1 protein, mouse
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Arginase