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.

Keywords: Atherosclerosis; Inflammation; Inflammatory disorders; Macrophages; Wnt5a.

Figure 1. Wnt signaling pathways

In the absence of canonical Wnt, cytoplasmic β-catenin is phosphorylated by glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α). These form a recognition complex that recruits other components of the “destruction complex” – AXIN and adenomatous polyposis coli (APC), to ubiquitinate β-catenin for proteasomal degradation. Interaction of canonical Wnts with Frizzled receptors and LRP 5/6 at the cell surface leads to recruitment and activation of the disheveled (DSH) protein. Active DSH inhibits the “destruction complex” proteins by recruiting AXIN to the cell plasma membrane, which binds to the cytoplasmic side of receptor-related protein 5/6 (LRP 5/6) co-receptors. This inhibits the degradation complex, promotes the accumulation of β-catenin and its translocation to the nucleus. Increased levels of nuclear β-catenin leads to transcriptional activation of target genes via interaction with DNA-bound transcriptional factors like T-cell factor/lymphoid enhancer factor (TCF/LEF). The β-catenin-independent pathways are activated by non-canonical Wnt and specific combinations of Frizzled receptors. One branch of the non-canonical pathway involves the activation of small GTPases – Rho and Rac; the DSH–Rho and DSH-Rac GTPase complexes activate JUN N-terminal kinase (JNK) to regulate the cell polarity pathway (PCP). Another branch, when activated, leads to phospholipase C (PLC)-mediated increases in intracellular Ca²⁺ levels that further activates Ca²⁺/calmodulin-dependent protein kinase (CAMKII) and protein kinase C (PKC). Both of these kinases can activate the nuclear factor of activated T cells (NFAT) transcription factor to regulate gene expression. This signaling branch has been shown to mediate cell proliferation, migration and movement. Also, both CAMKII and PKC can block the canonical Wnt–β-catenin pathway by inhibiting β-catenin-dependent transcription of target genes.

Figure 2. Working hypothesis of Wnt5a-mediated activation of macrophages that lead to inflammatory diseases

Toll-like receptor (TLR)- or oxidized-LDL (ox-LDL)-induced activation of macrophages leads to transcription of Wnt5a via (a) NFκB signaling, (b) Ca²⁺/calmodulin-dependent protein kinase (CAMKII) signaling, or (c) protein kinase C (PKC)- dependent signaling pathways. Wnt5a, when secreted, can work in a paracrine manner to prime endothelial cells, smooth muscle cells, or other cell types (e.g. lymphocytes) by interacting with the frizzled or Ror2 receptors. Induced Wnt5a further mediates up-regulation of inflammatory mediators like IL-6, TNF-α through activated NFκB signaling pathway. All of these events together, result in sustained release of Wnt5a and other pro-inflammatory cytokines that cause cell migration, proliferation and differentiation, which can result in a severe inflammatory response.