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).