title: Pathogen-specific TLR2 protein activation programs macrophages to induce Wnt-beta-catenin signaling.
abstract: Innate immunity recognizes and resists various pathogens; however, the mechanisms regulating pathogen versus nonpathogen discrimination are still imprecisely understood. Here, we demonstrate that pathogen-specific activation of TLR2 upon infection with Mycobacterium bovis BCG, in comparison with other pathogenic microbes, including Salmonella typhimurium and Staphylococcus aureus, programs macrophages for robust up-regulation of signaling cohorts of Wnt-β-catenin signaling. Signaling perturbations or genetic approaches suggest that infection-mediated stimulation of Wnt-β-catenin is vital for activation of Notch1 signaling. Interestingly, inducible NOS (iNOS) activity is pivotal for TLR2-mediated activation of Wnt-β-catenin signaling as iNOS(-/-) mice demonstrated compromised ability to trigger activation of Wnt-β-catenin signaling as well as Notch1-mediated cellular responses. Intriguingly, TLR2-driven integration of iNOS/NO, Wnt-β-catenin, and Notch1 signaling contributes to its capacity to regulate the battery of genes associated with T(Reg) cell lineage commitment. These findings reveal a role for differential stimulation of TLR2 in deciding the strength of Wnt-β-catenin signaling, which together with signals from Notch1 contributes toward the modulation of a defined set of effector functions in macrophages and thus establishes a conceptual framework for the development of novel therapeutics.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Kushagra
authors.initials: K
authors.lastname: Bansal
authors.forename: Jamma
authors.initials: J
authors.lastname: Trinath
authors.forename: Dipshikha
authors.initials: D
authors.lastname: Chakravortty
authors.forename: Shripad A
authors.initials: SA
authors.lastname: Patil
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology* / Q000378:metabolism; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D051153:Wnt Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051153:Wnt Proteins; D051176:beta Catenin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse