ReviewWnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses
Section snippets
Wnt signaling in inflammation: a new role for an ancient pathway
The Wnt pathway is an evolutionarily highly conserved fundamental signaling system which governs organ development as well as homeostatic processes in the adult (recently reviewed by Angers and Moon (2009), Gordon and Nusse (2006) and van Amerongen and Nusse (2009)). This comprises the regulation of proliferation, differentiation, apoptosis, motility and polarization of cells. Because Wnt signaling is involved in this diversity of essential functions, abnormal regulation leads to malformation,
Two prototype Wnts, Wnt3a and Wnt5a, have an opposing effect on Wnt/beta-Catenin signaling in murine bone-marrow-derived macrophages
We analyzed the responsiveness of murine bone-marrow-derived macrophages (BMDM) to these two prototype Wnts, Wnt3a and Wnt5a. The degree of activation with regard to the Wnt/beta-Catenin pathway was monitored on the level of total cellular beta-Catenin by Western blot and on the level of target gene expression by quantitative real-time PCR (qRT-PCR). As reported for other cell types, only Wnt3a – but not Wnt5a – led to an accumulation of beta-Catenin in murine BMDM (Fig. 2A and B). Beta-Catenin
Wnt/beta-Catenin signaling and inflammation reciprocally regulate one another in mycobacterial infections
A reciprocal regulation of Nuclear Factor-kappaB (NF-kappaB) and Wnt/beta-Catenin signaling might be important for reconstituting tissue homeostasis following inflammatory insults (Neumann et al., 2010). We observed that Wnt/beta-Catenin signaling was significantly reduced in lungs of M. tuberculosis-infected mice. This was accompanied by a downregulation of all Fzd receptors except Fzd1 and Fzd5. Remarkably, these two receptors were found to be induced during the course of infection. Fzd5 acts
Wnt3a and Wnt5a show a partially overlapping pattern of activating NF-kappaB and MAPK pathways
In addition to the Wnt/beta-Catenin pathway discussed above, several other signaling pathways can be induced by Wnts. In particular, the so called “non-canonical” signaling pathways, the Wnt/PCP and the Wnt/Ca2+ pathway, have been the focus of recent studies: the Wnt/Ca2+ pathway is induced by Wnt5a and activates the central inflammatory transcription factor NF-kappaB (Bradley and Drissi, 2010, Kim et al., 2010, Sen and Ghosh, 2008). The available data is yet limited but recent results of Kim
Wnt5a: of men, mice and zebrafish
Wnt5a clearly exerts pro-inflammatory properties on human macrophages, lymphocytes and also endothelial cells (Blumenthal et al., 2006, Pereira et al., 2008, Kim et al., 2010). These effects are corroborated when murine bone-marrow-derived macrophages of C57BL/6 origin are stimulated with recombinant murine Wnt5a alone or in combination with M. avium infection. As shown in Fig. 6A, the macrophages respond to recombinant Wnt5a with a dose-dependent increase of TNF-alpha mRNA levels (up to 4-fold
Concluding remarks
When one recapitulates all the reciprocal interferences of inflammatory processes and Wnt signaling, a complex picture of Wnt-mediated immunomodulation emerges (illustrated in Fig. 1, Fig. 7). Wnt-induced signals can have both, driving and inhibitory effects on inflammatory processes. Likewise, inflammatory signaling pathways interfere with Wnt-induced signals in a synergistic or antagonistic fashion. Additionally, infection or inflammation themselves induce components of Wnt signaling pathways
Acknowledgements
This work was supported in part by DFG grants SFB 415-C7 and EXC306 to NR and SE. The authors gratefully acknowledge K. Kopp, K. Seeger, S. Kröger and L. Dost for expert technical assistance.
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