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).