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Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis ‐infected macrophages
Author(s) -
Neumann Jan,
Schaale Kolja,
Farhat Katja,
Endermann Tobias,
Ulmer Artur J.,
Ehlers Stefan,
Reiling Norbert
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-160994
Subject(s) - wnt signaling pathway , biology , wnt3a , innate immune system , proinflammatory cytokine , tumor necrosis factor alpha , frizzled , microbiology and biotechnology , inflammation , signal transduction , mycobacterium tuberculosis , immune system , immunology , cancer research , tuberculosis , medicine , pathology
Wnt/Frizzled signaling, essential for embryonic development, has also recently been implicated in the modulation of inflammatory processes. In the current study, we observed a reciprocal regulation of the Toll‐like receptor (TLR)/nuclear factor‐κB (NF‐κB) and the Wnt/β‐catenin pathway after aerosol infection of mice with Mycobacterium tuberculosis : whereas proinflammatory mediators were substantially increased, β‐catenin signaling was significantly reduced. A systematic screen of Fzd homologs in infected mice identified Fzd1 mRNA to be significantly up‐regulated during the course of infection. In vitro infection of murine macrophages led to a strong induction of Fzd1 that was dependent on TLRs, the myeloid differentiation response gene 88 (MyD88), and a functional NF‐κB pathway. Flow cytometry demonstrated an elevated Fzdl expression on macrophages in response to M. tuberculosis that was synergistically enhanced in the presence of IFN‐γ. Addition of the Fzd1 ligand Wnt3a induced Wnt/β‐catenin signaling in murine macrophages that was inhibited in the presence of a soluble Fzd1/Fc fusion protein. Furthermore, Wnt3a reduced TNF release, suggesting that Wnt3a promotes anti‐inflammatory functions in murine macrophages. The current data support the notion that evolutionarily conserved Wnt/Fzd signaling is involved in balancing the inflammatory response to microbial stimulation of innate immune cells of vertebrate origin.—Neumann, J., Schaale, K., Farhat, K., Endermann, T., Ulmer, A. J., Ehlers, S., Reiling, N. Frizzledl is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis ‐infected macrophages. FASEB J . 24, 4599–4612 (2010). www.fasebj.org