Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogrammingMycobacterium tuberculosis‐infected macrophages

Abstract

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 Fzd1 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.

Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll‐like receptor 4

“…This is in concordance with the manufacturer's specifications (<1 EU/μg), as well as observations by others reporting Wnt3a-and Wnt5a-induced inflammatory responses in human monocytes and DCs [21,24]. Of note, we were unable to observe cytokine production by macrophages attributable to Wnt3a and Wnt5a using conditioned media from Wnt-overexpressing cell lines (data not shown), similar to a previous report that used Wnt3a-conditioned medium [18]. Thus, we sought further assurance that the cytokine-inducing properties of recombinant Wnt3a and Wnt5a were retained in macrophages deficient for TLR4 and the TLR adaptor, MyD88.…”

Wnt6 Is Expressed in Granulomatous Lesions of Mycobacterium tuberculosis–Infected Mice and Is Involved in Macrophage Differentiation and Proliferation

“…GSK3b inhibition, as it happens during activation of Wnt/b-catenin signaling, was shown to suppress proinflammatory cytokine expression in different experimental settings (18,19). This holds true also in mycobacterial infections, as we recently demonstrated the suppression of TNF-a expression in mycobacteria-infected macrophages by Wnt3a or inhibition of GSK3b, respectively (4,20).…”

“…Mice were sacrificed at days 1, 21, and 42 postinfection (p.i.). Analyses were performed as previously described (20).…”

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

“…50 In contrast, during acute inflammation Wnt5a is also involved in inducing anti-inflammatory effects from macrophages to prevent an excessive and harmful immune response. [50][51][52][53] These data imply that Wnt signaling is important to avoid overwhelming harmful inflammatory reactions in responses to acute infections. In contrast, Wnt ligands have shown no effect on the differentiation into alternative activated M2 macrophages.…”