Wnt5a: A player in the pathogenesis of atherosclerosis and other inflammatory disorders

Abstract

Objective The objective of this article is to review the current literature on Wnt5a and its signaling mechanism, along with its role in atherosclerosis. In addition, the significance of Wnt5a as a diagnostic marker and a potential therapeutic target is reviewed. Wnt5a, a secreted glycoprotein, belongs to a family of highly conserved proteins that regulate important processes such as cell fate specification, embryonic development, cell proliferation, migration, and differentiation in a variety of organisms. The complexity of Wnt5a signaling lies in the fact that Wnt5a can bind to different classes of frizzled receptors, receptor tyrosine kinase-like orphan receptor 2, as well as co-receptors such as low density lipoprotein receptor-related protein 5/6. Wnt5a signals primarily through the non-canonical pathway, where it mediates cell proliferation, adhesion, and movement. However, the role of Wnt5a in canonical signaling is still unresolved. Depending on the receptor availability, Wnt5a can serve to activate or inhibit the canonical Wnt signaling pathway. Due to the promiscuous nature of Wnt5a, it has been extremely difficult to fully understand its signaling mechanism. Wnt5a has recently emerged as a macrophage effector molecule that triggers inflammation. Perturbations in Wnt5a signaling have been reported in several inflammatory diseases, particularly in sepsis, rheumatoid arthritis, and atherosclerosis. Conclusion Both existing and emerging evidence suggests that the expression of Wnt5a is always up-regulated in these, and possibly other inflammatory disorders. This knowledge can be useful for targeting Wnt5a and/or its receptor and downstream signaling molecules for therapeutic intervention in inflammatory disorders.

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

“…However, we found by gene expression analysis that Fzd5, but not Wnt5a, was upregulated by Ehrlichia, suggesting that Ehrlichia regulates the expression of Wnt5a receptor instead of Wnt5a itself, although Wnt5a does appear to be important for bacterial survival after entry. Wnt5a can bind to different classes of receptors and coreceptors, but Wnt5a signals primarily through the noncanonical pathway, where it mediates cell proliferation, adhesion, and movement (56). However, the role of Wnt5a in canonical signaling is still unclear, due to its complex nature.…”

WNT5A-JNK regulation of vascular insulin resistance in human obesity

“…Recent clinical data have implicated aberrant WNT signaling in the pathogenesis of adult diseases such as cancer, arthritis, and cardiovascular disease. 14,16 …”

Wnt5a is expressed in spondyloarthritis and exerts opposite effects on enthesis and bone in murine organ and cell cultures

“…Indeed, depending on the receptor availability, Wnt5a can activate the noncanonical Wnt-Ca 21 and Wnt-planar cell polarity pathways, or activate the canonical pathway. 20 Further studies are needed to identify preponderant Wnt5a signaling pathways in our different models. Of note, the concentrations of Wnt5a that are commonly used in cell culture models are almost 100-fold superior to synovial fluid levels.…”

“…[18][19][20] Maeda et al indeed showed that among the 19 Wnt ligands, Wnt5a messenger RNA (mRNA) was the most upregulated Wnt member in mouse synovial tissues from collagen-induced arthritis. 19 In addition, although the canonical Wnt pathway appears to inhibit chondrocyte differentiation from mesenchymal precursors, 21,22 Wnt5a has been reported by several independent groups to induce chondrogenesis.…”