4.Wnt5a and inflammatory diseases
4.1 Wnt5a and sepsis
Sepsis is a complicated and severe disease characterized by infection of the systemic inflammatory response, leading to diffuse intravascular coagulation and shock (60). The researchers confirmed the role of Wnt5a in sepsis and found that the level of Wnt5a protein in patients are significantly increased, and the serum concentration of Wnt5a in patients with sepsis was positively correlated with the severity of the disease; its decrease or increase positively correlated with the improvement or deterioration of the disease (48,61-62). Pereira et al. also reported a significant increase in Wnt5a levels in serum and bone marrow macrophages in patients with sepsis, and confirmed that the inflammatory signaling axis (Wnt5a/FZD5/CaMKII) played a crucial role in the inflammatory reaction of macrophages. Their study also found that Wnt5a recombinant protein stimulated the release of proinflammatory cytokines in macrophages such as IL-1β, IL-6, IL-8 and MIP-1b, which were inhibited in cells pretreated with activated protein C (APC) (55). In another study, Bergenfield et al. also found that Wnt5a induces immunosuppressive macrophages in a proinflammatory state, and that the phenotype of these immunosuppressive cells are similar to that of recombinant monocytes in patients with sepsis. It was also found that Wnt5a-induced feedback inhibition was closely related to IL-10-induced inhibition of the classical TLR4-NF-κB signaling pathway in macrophages of patients with gram-negative bacteria or LPS induced sepsis (58). Results from Jungho Shin’s team showed that Wnt5a levels were significantly elevated in patients with urinary sepsis, and assessing Wnt5a levels may help predict the occurrence of major renal adverse events and renal recovery in these patients (63). Ye, J et al. also found that miR-23a-3p inhibited sepsis-induced kidney epithelial cell injury by suppressing Wnt/β-catenin signaling by targeting wnt5a (64).
4.2 Wnt5a and asthma
Asthma is a chronic airway disease characterized by chronic airway inflammation, airway hyperresponsiveness, and irreversible airway remodeling (65). Katharina Dietz et al. found that the expression of Wnt5a, transglutaminase 2 and leukotriene in asthmatic airway inflammation, was age-related and correlated with age-related hormone resistance in asthmatic patients, which may be a potential new therapeutic target for airway inflammation and remodeling (66). Besides, studies have shown that Wnt5a is abundant in airway smooth muscle cells, and there is also a significant rise of TGF-β1, which promotes the expression of collagen protein and fiber connections. It is suggested that Wnt5a may be involved in airway remodeling of asthmatic patients, and Wnt5a is also involved in regulating airway smooth muscle, which may suggest a relationship of airway hyperresponsiveness in asthma (67). Andrius Januskevicius et al. have shown that eosinophils enhance the expression of Wnt5a, TGF-β1, fibronectin, and collagen genes in airway smooth muscle cells of asthmatic patients, suggesting Wnt5a may be involved in eosinophil-mediated airway remodeling (68). Studies have also confirmed that the expression of Wnt5a/JNK signaling pathway-related molecules in the lung tissues of asthmatic rats are enhanced, and the expressions of Wnt5a mRNA、p-JNK、p-c-Jun proteins are significantly increased, which may be related to the inflammatory response of bronchial asthma (69). Furthermore, studies on peripheral blood mononuclear lymphocytes of asthmatic patients have verified that Wnt5a, thymus, and activation-regulated chemokines, macrophage-derived chemokines and eosinophil activated chemokines 3 can be used as potential biomarkers for anti-IL-13 therapy (70). Liu Na’s team found that, in the asthma group of mice, worsened subepithelial fibrosis was associated with increased TGF-β1 and Wnt5a compared with the control group, which may be related to airway remodeling in asthma (71). Xiaoshun Ai et al. have also proposed a diagnostic model of 10 macrophage-related genes, including Wnt5a, to predict asthma risk. The expression of Wnt5a in the control group was lower than that in the asthma group (72).
In conclusion, Wnt5a is associated with eosinophil effect, airway hyperresponsiveness, and airway remodeling in the pathogenesis of bronchial asthma, which can provide a new idea for the treatment of asthma.
4.3 Wnt5a and COPD
COPD is a preventable and treatable disease of airway inflammation characterized by continuous airflow limitation (73). Hoeke a. Baarsma et al. showed that the Wnt5a signaling pathway impaired endogenous pulmonary repair in COPD and the overexpression of pulmonary-specific Wnt5a in vivo experiments aggravated the air expansion of elastase-induced emphysema (74). Thus, a new and important mechanism of impaired mesenchymal-epithelial cross-linking has been identified for the treatment of COPD. Studies by Diana Feller’s team have shown that Wnt5a and proinflammatory cytokines can be transported in lipid bilayer enclosed extracellular vesicles that can reach every organ in patients with COPD, indicating the underlying systemic mechanism of this disease and also the difficulty in controlling COPD (75). Additionally, studies have shown that inhibition of the Wnt5a/JNKl pathway by Sfrp5 can combat the inflammatory response in the rat model of insulin resistance combined with COPD, which may be a new target for the treatment of COPD (76). Recently, Xiuli Zhang et al. have shown that microRNA-149-3p can regulate the expression of Wnt5a, causing changes in the expression of alveolar inflammatory factors, and further affecting the development of COPD (77).
4.4 Wnt5a and tuberculosis
Tuberculosis, a pulmonary infectious inflammatory disease caused by Mycobacterium
tuberculosis, is one of the leading causes of infectious death in the world (78). The Wnt signaling pathway has been shown to play an immunoregulation role in a variety of inflammatory and infectious diseases, including tuberculosis. Blumenthal et al. found that Wnt5a and its putative receptor FZD5 exist in lung biopsies of tuberculosis patients. Mycobacterium induces the expression of macrophage Wnt5a in a TLR-NF-κB-dependent way, and Wnt5a has an immunoregulation function on immune cells (53). Junwei Cui et al. have shown that Wnt5a overexpression can reverse the effects of liver kinase B1 on the intracellular survival of mycobacterium and the release of inflammatory cytokines, and plays an important role in controlling mycobacterium and cellular inflammation (79). In addition to human and mouse cells, increased Wnt5a expression was observed in adult zebrafish infected with Mycobacterium saltwater, suggesting that Wnt5a induction after infection is a conserved mechanism (80). By activating innate immune cells, Wnt5a plays an important regulatory role in the host’s response to Mycobacterium tuberculosis infection, thereby directly affecting the function of adaptive immune cells. Interestingly, however, Deming Chen’s latest study reveals the opposite idea that Wnt5a is reduced in both humans and mice during Mycobacterium tuberculosis infection and the effect of Wnt5a reduction on Mycobacterium tuberculosis infection in mice and its biological significance. Wnt5a deficiency in Mycobacterium tuberculosis-infected macrophages regulates the secretion, polarization, and apoptosis of inflammatory cytokines, thereby shielding the macrophages themselves from multidrug-resistant tuberculosis infection (81).
Thus, the expression of Wnt5a in the pathogenesis of tuberculosis and its mechanism are still unclear, and further experimental studies are needed to verify.
4.5 Wnt5a and rheumatoid arthritis
Rheumatoid arthritis is a chronic autoimmune disease of unknown origin that is associated with inflammation of the joints and causes gradual destruction of articular cartilage and bone (82). The inflammatory response of the synovial membrane induces changes in macrophages and synovial fibroblasts derived from bone marrow cells, leading to the secretion and expression of various inflammatory mediators (83,84). For example, Sen et al. used Western-Blot analysis to show that the RNA levels of Wnt5a and FZD5 in synovial tissue of rheumatoid arthritis were increased compared with the normal adult control group. Results show that compared with the normal synovial fibroblasts, IL-6, IL-8, IL-15 expression level is higher in the cultured fibroblasts, rheumatoid arthritis synovial cells, and the expression pattern of cytokines was replicated in normal fibroblasts transfected with Wnt5a expression vector, suggesting that the Wnt5a/FZD5 signaling pathway in the synovial membrane of rheumatoid arthritis may be a new target for therapeutic intervention (85). By inhibiting the Wnt5a/FZD5 signaling pathway, the activation of fibroblasts in the rheumatoid synovial was inhibited, and the expression of IL-6, IL-15 and NF-κB ligand (RANKL) receptor activators in the cells were down-regulated, which further confirmed that Wnt5a participated in the inflammatory response in the pathogenesis of rheumatoid arthritis (86). Angela Rodriguez-Trillo et al. indicated that Wnt5a contributes to the enhanced migration and invasiveness of rheumatoid arthritis fibroblast-like synoviocytes through Ryk and the specific activation of Ras homolog gene family member A leads to Rho-Kinase and downstream kinases (87). Results from Dorra Elhaj Mahmoud’s team showed that Wnt5a-induced inflammation was significantly activited in the presence of SFRP5, stimulating the expression of pro-inflammatory targets in tissue-derived fibroblast-like synoviocytes from patients with
rheumatoid arthritis (88).
4.6 Wnt5a and atherosclerosis
Atherosclerosis lesions are based on lipid deposition caused by lipid metabolism disorders, characterized by the fact that the lesion of the involved artery starts from the intimal layer and is the main cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. In the late 20th century, Ross proposed that atherosclerosis is an inflammatory disease characterized by the aggregation of macrophages in the intima (89). Immunohistochemical analysis showed that Wnt5a was highly expressed in human and mouse atherosclerotic lesions, especially in the macrophage filling area, consistent with the expression of TLR-4 (90,91). The induction of Wnt5a may be related to oxidized low-density lipoprotein, which can stimulate the expression of Wnt5a in human macrophages in vitro (92). Adipose tissue-derived Wnt5a regulates obesity vascular redox signaling through USP17/RAC1-mediated Nicotinamide adenine dinucleotide phosphate oxidase activation (93). Similarly, Malgor et al. found that Wnt5a, TLR-2, and TLR-4 were increased in advanced human atherosclerotic lesions (87). Besides, Wnt5a stimulates proliferating and calcifying endothelial cells, both of which are involved in the pathogenesis of atherosclerosis (94-97). Some research teams have found that the Wnt5a protein level is positively correlated with the calcification degree of smooth muscle cells, which is mediated by the Wnt5a/Ror2 signaling mechanism (97). Qin also showed that Wnt5a can reduce cholesterol accumulation by regulating the reverse transport of cholesterol in macrophages (98). Consistent with these in vitro results, silencing Wnt5a inhibits NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways to attenuate atherosclerotic inflammation in vivo experiments in mice (99). Moreover, studies have shown that the Wnt5a level of serum in atherosclerosis patients is significantly higher than that in healthy people, and it is related to the severity of atherosclerosis (90,91). Moreover, Wnt5a has been verified to be involved in vascular calcification, which is a marker of advanced atherosclerosis and can be used as a biomarker to reflect the stages of atherosclerosis (96). Another major finding was that anti-Wnt5a therapy inhibited the development of atherosclerosis in mice of apolipoprotein e deficiency and reduced the expression of inflammatory cytokines (99). The results of Futao Zhang’s team showed that Wnt5a was verified as the target of miR-141-3p in vascular smooth muscle cells in an In Vitro Model of Atherosclerosis. PcDNA3-Wnt5a partially reversed the action of miR-141-3p mimic in oxidized- stimulated low-density lipoprotein vascular smooth muscle cells (100). Sara Awan’s team found that Wnt5a senses changes in dietary cholesterol supply and promotes lysosomal cholesterol export to the endoplasmic reticulum, thereby avoiding the formation of atherosclerosis through increasing lysosomal acid lipase expression, reducing the metabolic signal of mTORC1 kinase, and binding to Niemann–Pick C1 (NPC1) and NPC2 (101). Shi, Y et al. also fund that the Wnt5a/Ror2/PKC signaling pathway may be a potential and promising therapeutic target for the prevention and treatment of vascular proliferative diseases (102). Studies have shown that the dedicator of cytokinesis 9-AS2 promoted the proliferation and migration of vascular smooth muscle cells in atherosclerosis through regulating Wnt5a by targeting LIN28B (103).
These results indicate that Wnt5a is involved in the inflammatory response inatherogenesis and calcification, the level of Wnt5a in serum can reflect the severity and stage of atherosclerosis, it can also inhibit the inflammatory response of atherosclerotic plaque formation by regulating the expression of Wnt5a. Therefore, anti-Wnt5a targeted therapy may become a new therapy for atherosclerosis.
4.7 Wnt5a and psoriasis Vulgaris
Psoriasis Vulgaris is a chronic inflammatory skin disease that affects 1 to 3 percent of the population (104). The cellular response includes neutrophils, macrophages, dendritic cells, epidermal keratinocytes, and a group of T lymphocytes (105). Studies have shown that Wnt5a is significantly increased in psoriatic plaques (106,107). Similarly, Romanowska et al. reported that Wnt5a and FZD5 were overexpressed in human psoriasis skin lesions and redistributed in the psoriasis epidermis, which was related to the disorder of keratinocytes differentiation (108). Wnt5a functionally enhances the proinflammatory signaling pathway of interferon, it synergistically increases the expression of type 1 interferon target genes nedd8, ubiquitin-like protein, and amyloid precursor proteins by reducing the concentration of interferon required to induce these target genes in stimulated keratinocytes (108,109). Gene expression profiles of patients who responded to treatment without significant scarring, some genes associated with psoriasis, including Wnt5a, did not return to baseline after 3 months of treatment with etanercept, this indicates that even if the epidermal response to psoriasis is completely resolved, there is still an inflammatory gene consisting of a ”residual disease gene” (110). Therefore, it is suggested that the histological resolution of psoriasis lesions should be accompanied by gene map analysis to prevent recurrence, which will provide some evidence for the clinical management of psoriasis. Xiaoying Ning’s team found that Wnt5a was highly expressed in psoriasis lesions and was positively correlated with the severity of psoriasis, which may be one of the immunohistochemical predictors of the severity of psoriasis (111).