Pathogen-specific TLR2 Protein Activation Programs Macrophages to Induce Wnt-β-Catenin Signaling*

Bansal, Kushagra ; Trinath, Jamma ; Chakravortty, Dipshikha ; Patil, Shripad A. ; Balaji, Kithiganahalli Narayanaswamy (2011) Pathogen-specific TLR2 Protein Activation Programs Macrophages to Induce Wnt-β-Catenin Signaling* Journal of Biological Chemistry, 286 (42). pp. 37032-37044. ISSN 0021-9258

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Official URL: http://doi.org/10.1074/jbc.M111.260414

Related URL: http://dx.doi.org/10.1074/jbc.M111.260414

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 TReg 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.

Item Type:Article
Source:Copyright of this article belongs to American Society for Biochemistry and Molecular Biology.
Keywords:Bacteria; Innate Immunity; Macrophages; Signal Transduction; Toll-like Receptors (TLR); Wnt Pathway.
ID Code:118412
Deposited On:21 May 2021 06:03
Last Modified:02 Feb 2023 06:07

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