Wnt proteins differenzially regulate macrophage functions in the context of M. tuberculosis infection

Abstract

Wnt proteins are secreted palmitoylated glycoproteins with multiple functions in cell proliferation, migration as well as tissue organization. They are best known for their role in embryonic development and tissue homeostasis. We have recently identified Wnt5a and Frizzled5 to be functionally involved in the regulation of the Th1 cytokine response indicating a role in antimicrobial defense (Blumenthal et al, Blood 2006). In a systematic screen of Wnt/Fzd homologs in murine bone marrow derived macrophages, we have now identified Frizzled1 to be upregulated in response to mycobacteria and conserved bacterial structures. We show that increased Fzd1 transcription was dependent on TLR2, MyD88, NF-kappaB and TNF-alpha release. Macrophage Fzd1 expression was confirmed on protein level by Western blot and on a single cell level by FACS analysis. Infection of bone marrow derived macrophages with M. tuberculosis led to enhanced Fzd1 surface expression. In lung homogenates of M. tuberculosis infected mice Fzd1 mRNA was shown to be upregulated, whereas transcripts of its putative ligand Wnt3a were found constitutively expressed. By immunohistochemistry the localisation of Fzd1 and Wnt3a expressing cells was addressed. Functional studies revealed that Wnt3a-induced Wnt/beta-catenin signaling in macrophages was inhibited by a soluble Fzd1 fusion protein. Activation of Wnt/beta-catenin signaling modulated the immune response of macrophages to mycobacterial infection. Both Toll and Wnt signaling pathways are evolutionarily highly conserved and have only recently been found to intersect in Drosophila. The current data further support the notion that Wnt/Fzd signaling is involved in orchestrating the immune response due to microbial stimulation of innate immune cells.