Pathogen-specific TLR2 protein activation programs macrophages to induce Wnt-beta-catenin signaling

J Biol Chem. 2011 Oct 21;286(42):37032-44. doi: 10.1074/jbc.M111.260414. Epub 2011 Aug 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Bacteria / immunology*
  • Bacteria / metabolism
  • Bacterial Infections / genetics
  • Bacterial Infections / immunology*
  • Bacterial Infections / metabolism
  • Cell Line
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / microbiology
  • Mice
  • Mice, Knockout
  • Nitric Oxide Synthase Type II / biosynthesis
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / immunology
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / immunology
  • Receptor, Notch1 / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / microbiology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 2 / metabolism
  • Up-Regulation / genetics
  • Up-Regulation / immunology
  • Wnt Proteins / genetics
  • Wnt Proteins / immunology*
  • Wnt Proteins / metabolism
  • beta Catenin / genetics
  • beta Catenin / immunology*
  • beta Catenin / metabolism


  • Notch1 protein, mouse
  • Receptor, Notch1
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Wnt Proteins
  • beta Catenin
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse