Wnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses

doi:10.1016/j.ejcb.2010.11.004

European Journal of Cell Biology

Volume 90, Issues 6–7, June–July 2011, Pages 553-559

https://doi.org/10.1016/j.ejcb.2010.11.004 Get rights and content

Abstract

Wnt proteins are secreted, palmitoylated glycoproteins with multiple functions in cell proliferation and migration as well as tissue organization. They are best known for their role in embryonic development and tissue homeostasis. In the last years, Wnt signaling was also shown to be involved in the regulation of inflammatory processes: Wnt5a is induced in human macrophages in response to mycobacteria and conserved bacterial structures and contributes to the regulation of pro-inflammatory cytokines via its receptor Frizzled (Fzd) 5. Wnt5a is also induced in other infectious and inflammatory diseases such as tuberculosis, sepsis, psoriasis, rheumatoid arthritis and atherosclerosis. In contrast, Wnt3a, a ligand of Fzd1, is constitutively expressed by bronchial epithelial cells and mediates anti-inflammatory effects on mycobacteria-infected macrophages via the Wnt/beta-Catenin signaling pathway. This pathway suppresses the activity of GSK3beta, a well known regulator of NF-kappaB-dependent gene transcription. Here we review recent data on immunomodulatory activities of Wnt proteins. Additional experiments using exogenous Wnt homologs further support the notion that TLR/NF-kappaB and Wnt signaling are functionally interconnected.

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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ReviewWnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses

Abstract

Section snippets

Wnt signaling in inflammation: a new role for an ancient pathway

Two prototype Wnts, Wnt3a and Wnt5a, have an opposing effect on Wnt/beta-Catenin signaling in murine bone-marrow-derived macrophages

Wnt/beta-Catenin signaling and inflammation reciprocally regulate one another in mycobacterial infections

Wnt3a and Wnt5a show a partially overlapping pattern of activating NF-kappaB and MAPK pathways

Wnt5a: of men, mice and zebrafish

Concluding remarks

Acknowledgements

J. Biol. Chem.

Blood

J. Biol. Chem.

J. Biol. Chem.

J. Invest. Dermatol.

Trends Genet.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

Dev. Cell.

Exp. Hematol.

J. Invest. Dermatol.

Trends Genet.

Cancer Cell

Mol. Immunol.

Dev. Cell

Cell Signal.

Cancer Cell

Mol. Immunol.

Proximal events in Wnt signal transduction

Nat. Rev. Mol. Cell Biol.

p38 mitogen-activated protein kinase regulates canonical Wnt-beta-catenin signaling by inactivation of GSK3beta

J. Cell Sci.

Mitogen-activated protein kinases and Wnt/beta-catenin signaling: molecular conversations among signaling pathways

Commun. Integr. Biol.

WNT5A regulates chondrocyte differentiation through differential use of the CaN/NFAT and IKK/NF-{kappa}B pathways

Mol. Endocrinol.

Essential role of Wnt3a-mediated activation of mitogen-activated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralization in C3H10T1/2 mesenchymal cells

Endocrinology

Wnt5a is expressed in murine and human atherosclerotic lesions

Am. J. Physiol.-Heart Circ. Physiol.

The making of Wnt: new insights into Wnt maturation, sorting and secretion

Development

Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains

Nature

Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells

Mol. Cell. Biol.

Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation

Shock

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

Oncogene

Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response

Oncogene

Review
Wnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses

Wnt-5a/Ca²⁺-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1alpha signaling in human mammary epithelial cells