3. The relationship of Wnt5a and inflammatory factors.
Wnt5a has been recognized as a proinflammatory factor widely based on its
induction of proinflammatory cytokines and chemokines in different cells such as macrophages, endothelial cells, pulp cells , marrow stroma cells, synovioblasts, and other cell types (47). Upon lipopolysaccharide (LPS) stimulation, increased production of Wnt5a in macrophages has been found, which induces the expression of intracellular IL-1β, IL-6, IL-8, macrophage inflammatory protein-1b (MIP-1b) and other proinflammatory factors (48). Wnt5a can also induce chemokines such as CCL2 and IL-8, which can recruit macrophages and neutrophils and amplify the inflammatory reaction (5,48-52). Besides, Wnt5a Has been reported to induce Cyclooxygenase (COX)-2 production; and knocking out or blocking Wnt5a can reduce the production of COX-2 (52), so Wnt5a can be a target of the inhibition of COX-2. Furthermore, Wnt5a is upregulated after mycobacterium infection and regulates the inflammatory response of IL-12 in human monocytes with binding to the FZD5 receptor (48,53). Similarly, Valencia et al. have shown that Wnt5a gene knockout leads to a significant decrease in IL-12 expression in mature dendritic cells (54). Kim et al. confirmed in another study that Wnt5a upregulates IL-1α、IL-3, and other cytokines in cultured endothelial cells by activating the NF-κB signaling pathway (5). The comprehensive analysis of the Wnt signaling pathway mediated by cytokines and the proinflammatory signaling pathways further support the role of Wnt5a as a biomarker in the diagnosis, severity assessment, and prognosis of inflammatory diseases. In addition, studies have shown that Wnt5a increases the invasiveness of melanoma cells through activating PKC signaling pathway (43). To further support the proinflammatory signaling function of the non-canonical Wnt signaling pathway, Catalan et al. have demonstrated that activation of non-canonical Wnt signaling through Wnt5a can activate the inflammatory response of visceral adipose tissue in obese subjects(55,56). Similarly, the Wnt5a-mediated non-canonical Wnt signaling pathway has been shown to increase inflammation in adipose tissue through activating the JNK pathway by promoting the expression of macrophage proinflammatory cytokines (56). Interestingly, Wnt5a not only increases the expression of proinflammatory cytokines, but also acts on cells to induce the increase of Wnt5a production. For example, Rauner et al. showed that Wnt5a expression in human marrow stromal cells was significantly increased. Other experiments have confirmed that TNF-α can also regulate Wnt5a overexpression in mesenchymal stem cells, fat cells, and human pulp cells. Moreover, it has been found that the stimulation of IL-6 on melanoma cells can also induce Wnt5a overexpression in a dose-dependent manner (51-52,55,57-58). In conclusion, the interaction between Wnt5a and proinflammatory cytokines can be enhanced and amplified in different cells.
Although a large number of literatures have reported that Wnt5a can promote the expression of inflammatory cytokines, but some studies have also shown that Wnt5a can induce the expression of anti-inflammatory factors in some special conditions. Bergenfield et al. reported that Wnt5a, which is highly expressed in proinflammatory M1-type macrophages of sepsis patients, can promote the expression of IL-10, and inhibit the production of IL-6, IL-8, and IL-12, which plays an anti-inflammatory role (59).
In conclusion, the above studies confirmed the proinflammatory function of Wnt5a, suggesting that Wnt5a pathway may be a potential candidate target for therapeutic intervention in inflammatory diseases, however, Wnt5a’s inflammatory signal transduction pathway is complex, and there are actions and reactions between Wnt5a and proinflammatory factors, so its mechanism of action in inflammatory diseases needs to be further studied (Figure 1). Studies in recent years have shown that Wnt5a is involved in a variety of inflammatory diseases including bronchial asthma, chronic obstructive pulmonary disease, sepsis, rheumatoid arthritis, atherosclerosis, psoriasis Vulgare, and tuberculosis. Here we review the mechanism of Wnt5a in the pathogenesis in these inflammatory diseases (Table 1).