title: Wnt6 is expressed in granulomatous lesions of Mycobacterium tuberculosis-infected mice and is involved in macrophage differentiation and proliferation.
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.
authors.affiliation: Division of Microbial Interface Biology, Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23845 Borstel, Germany;
authors.forename: Kolja
authors.initials: K
authors.lastname: Schaale
authors.forename: Julius
authors.initials: J
authors.lastname: Brandenburg
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006099:Granuloma / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D037342:Pertussis Toxin / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000276:immunology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; C489428:Myc protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; C095936:Wnt6 protein, mouse; D051176:beta Catenin; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; C544448:Arg1 protein, mouse; D001119:Arginase