doi: 10.1161/ATVBAHA.107.160952
© 2008 American Heart Association, Inc.
Editorial |
Wnt Pathway
A New Role in Regulation of Inflammation
From the Bristol Heart Institute, Bristol Royal Infirmary, UK.
Correspondence to Sarah Jane George, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom. E-mail s.j.george{at}bris.ac.uk
The Wnt pathway plays a critical role in the development of multicellular organisms.1,2 It shows evolutionary conservation across a wide range of species, ranging from the freshwater polyp Hydra to worms, flies, and vertebrates. Since the 1980s our knowledge of Wnt signal transduction has expanded tremendously. This family of proteins comprises a group of 19 secreted lipid-modified glycoproteins that not only play a crucial role in the regulation of embryogenesis and development but also cell proliferation, differentiation, polarity, migration, and invasion.1,2 Abnormal Wnt signaling has been associated with many human diseases, ranging from cancer to degenerative diseases. Thus studies of Wnt signaling have opened up new avenues in biomedical research, including molecular embryology, stem cell biology, tumorigenesis, regenerative medicine, and rational drug discovery.3 Interestingly, in this issue of Arteriosclerosis Thrombosis and Vascular Biology, Pereira and colleagues highlight the involvement of the Wnt pathway in the sustained inflammation in sepsis. This study contributes to the accumulating evidence that the Wnt pathway also plays a distinct role in inflammation and immunity.
See accompanying article on page 504
Pereira and colleagues suggest that Wnt5a is a highly specific autocrine and paracrine macrophage-derived effector molecule which triggers inflammation. Altered macrophage functions contribute to the pathogenesis of many infectious, immunologic, and inflammatory disease processes in addition to sepsis, such as rheumatoid arthritis and atherosclerosis. Development of novel pharmacological modulators of macrophage activity represents an important strategy for the prevention and treatment of these inflammation-related diseases. Consequently the findings of Pereira and colleagues may have wider impact by relevance to other pathological conditions which involve inflammation. Additionally these findings indicate that Wnt5a is an attractive candidate for therapeutic intervention in inflammatory diseases.
Genomic studies have detected upregulation of Wnt5a in macrophages and dendritic cells exposed to pathogens4,5 and during differentiation of monocytes into dendritic cells after exposure to GM-colony stimulating factor (CSF) and interleukin (IL)-4.6 Together, this suggests that Wnt5a expression contributes to innate and adaptive immune responses. In support of this, upregulation of Wnt5a has been observed in pathological conditions involving inflammation such as rheumatoid arthritis7 and in tumor associated macrophages.8 One of the first direct indicators for the involvement of the Wnt pathway in inflammation and immunity was obtained from a study in Drosophila. Gordon and colleagues illustrated that the Drosophila Wnt protein family member WntD is upregulated in the fly via Toll/nuclear factor-
B (NF-B) signaling and is involved in the innate immune system.9 A subsequent study in human mononuclear cells demonstrated upregulation of Wnt5a in response to microbial stimulation required Toll/NF-B activation, indicating a similar mechanism in man.10 Interestingly, this study also demonstrated that Wnt5a upregulates the microbially-induced IL-12 response of antigen-presenting cells and IFN-
production by mycobacterial antigen-stimulated T-cells, illustrating a functional involvement in the antimicrobial defense.10 This was the first implication of the involvement of Wnt signaling in bridging innate and adaptive immunity to infections. In this recent study by Pereira and colleagues utilizing an in vitro model of inflammatory macrophage activation, additional support for a role of Wnt5a in sustained macrophage activation is provided. Macrophages stimulated with interferon (INF)- and endotoxin (LPS) consistently upregulated Wnt5a via Toll-like receptor activation. Wnt5a in turn upregulated expression of the proinflammatory genes, IL-6, IL-1β, IL-8, and macrophage inflammatory protein-1β (MIP-1β). Attenuation of these effects by activated protein C (APC) and the antiinflammatory cytokine IL-10 imply an active role of Wnt5a in the inflammatory response. Although these findings are not the first demonstration that Wnt5a regulates macrophage activation, this study is the first to provide a direct demonstration of relevance to pathological inflammation by showing higher levels of Wnt5a in patients with severe sepsis than healthy subjects.
Membership in the Wnt family is defined by amino acid sequence rather than functional properties. It is therefore not surprising that Wnts are associated with a number of different activities and downstream signaling pathways. The intracellular responses triggered by Wnts binding to their receptors, the Frizzled family of proteins, and activation of the key intermediate Dishevelled, are classified as canonical and noncanonical.11 The canonical signaling blocks degradation of cytosolic β-catenin and hence activates β-catenin/TCF transcriptional responses. This pathway is well characterized and involves the inhibition of glycogen synthase kinase-3β (GSK-3β) activity, translocation of β-catenin to the nucleus, and binding to nuclear transcription factor T cell factor (TCF).12 As a consequence it is responsible for the regulation of more than 50 mammalian genes. Initially, noncanonical signaling which is less well-defined was primarily associated with modulation of cell movement. It is β-catenin independent and activates the Wnt/Ca2+ and Wnt/planar cell polarity pathways. Evidence in flies and vertebrates points toward a complete separation of the canonical and noncanonical pathways downstream of Dishevelled.12 Noncanonical Wnts cause intracellular calcium flux leading to activation of Ca2+-dependent effector molecules such as calcium/calmodulin dependent kinase II (CamKII), nuclear factor associated with T cells (NFAT), and proteins kinase C (PKC) in a pertussis toxin (PTX)-sensitive manner. Because NFAT is associated with regulation of various genes including cytokines, cell cycle, differentiation, and apoptosis,13 the noncanonical pathway can modulate cell behavior via gene transcription.
Pereira and colleagues illustrate that Wnt5a activates CaMKII noncanonical signaling. Although not shown in this article, CAMKII activation may result in the activation of NFAT-dependent transcription as observed previously6 and lead thereby to the observed upregulation of cytokine expression. This study has raised awareness of the potential involvement of activation of noncanonical signaling via Wnt5a in inflammation. However, it appears this may only be the tip of the iceberg. Despite its classification as a noncanonical Wnt, recent evidence suggests that Wnt5a can also activate or inhibit canonical signaling depending on the receptor context.14 The ability of canonical signaling to upregulate the expression of several Wnt/β-catenin responsive genes in monocytes has raised the possibility that this pathway may also contribute to inflammation.15 Future studies are required, however, to provide direct information on the contribution of canonical signaling to the inflammatory response. Additionally, these initial studies have focused on Wnt5a, and there may be further involvement of this pathway via other Wnt proteins. Finally, it is highly probable that expression of Wnts from macrophages and dendritic cells has numerous affects on the behavior of the resident tissue cells via activation of canonical or noncanonical signaling. For example, cell death,16,17 proliferation,17–21 migration,21 and invasion22 of cell types adjacent to the macrophage including vascular smooth muscle cells and endothelial cells may also be affected by increased release of Wnt proteins by macrophages.
In summary our current knowledge strongly supports the involvement of Wnt5a signaling in the inflammatory response (see Figure). There is substantial evidence for the upregulation of Wnt5a by pathogens which leads to activation of noncanonical signaling in macrophages. It is likely, however, that future studies will reveal a more extensive role of this pathway in inflammatory diseases. A greater understanding of the modulators of Wnt expression and the noncanonical and canonical effects of Wnt proteins on inflammatory and resident cells will be paramount to clarifying the role of this pathway and perhaps enable the design of novel anti-inflammatory treatments.
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Disclosures
None.
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