Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis-infected macrophages

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-kappa B (NF-kappa B) and the Wnt/beta-catenin pathway after aerosol infection of mice with Mycobacterium tuberculosis: whereas proinflammatory mediators were substantially increased, beta-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-kappa B pathway. Flow cytometry demonstrated an elevated Fzd1 expression on macrophages in response to M. tuberculosis that was synergistically enhanced in the presence of IFN-gamma. Addition of the Fzd1 ligand Wnt3a induced Wnt/beta-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. Frizzled1 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