Noncanonical WNT-5B signaling induces inflammatory responses in human lung fibroblasts

Abstract

COPD is a progressive chronic lung disease characterized by pulmonary inflammation. Several recent studies indicate aberrant expression of WNT ligands and Frizzled receptors in the disease. For example, WNT-5A/B ligand expression was recently found to be increased in lung fibroblasts of COPD patients. However, possible effects of WNT-5A and WNT-5B on inflammation have not been investigated yet. In this study, we assessed the regulation of inflammatory cytokine release in response to WNT-5A/B signaling in human lung fibroblasts. Primary human fetal lung fibroblasts (MRC-5), and primary lung fibroblasts from COPD patients and non-COPD controls were treated with recombinant WNT-5A or WNT-5B to assess IL-6 and CXCL8 cytokine secretion and gene expression levels. Following WNT-5B, and to a lesser extent WNT-5A stimulation, fibroblasts showed increased IL-6 and CXCL8 cytokine secretion and mRNA expression. WNT-5B-mediated IL-6 and CXCL8 release was higher in fibroblasts from COPD patients than in non-COPD controls. In MRC-5 fibroblasts, WNT-5B-induced CXCL8 release was mediated primarily via the Frizzled-2 receptor and TAK1 signaling, whereas canonical β-catenin signaling was not involved. In further support of noncanonical signaling, we showed activation of JNK, p38, and p65 NF-κB by WNT-5B. Furthermore, inhibition of JNK and p38 prevented WNT-5B-induced IL-6 and CXCL8 secretion, whereas IKK inhibition prevented CXCL8 secretion only, indicating distinct pathways for WNT-5B-induced IL-6 and CXCL8 release. WNT-5B induces IL-6 and CXCL8 secretion in pulmonary fibroblasts. In summary, WNT-5B mediates this via Frizzled-2 and TAK1. As WNT-5 signaling is increased in COPD, this WNT-5-induced inflammatory response could represent a therapeutic target.

Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

“…Such an upregulated Wnt5B and remodeling-related gene expression were also observed in the air-liquid interface- (ALI-) cultured PBEC cell model, particularly in the cells from COPD patients [50]. In line with this finding, van Dijk et al recently demonstrated that Wnt5B induced inflammatory responses in human lung fibroblasts [53]. In this study, the authors ascertained inflammatory cytokine releases of human lung fibroblasts, and their results showed that Wnt5B had an ability to induce CXCL8 release in MRC-5 human fibroblasts upon Wnt5A/B simulation.…”

“…Importantly, canonical Wnt signaling activity was decreased in experimental emphysema mouse models, and an activation of Wnt/ β -catenin activation using lithium chloride (LiCl) led to an attenuation of experimental emphysema, as ascertained by an elevated expression of alveolar epithelial cell markers, decreased airspace enlargement, reduced collagen contents, and improved lung function [14]. Apart from Wnt/ β -catenin signaling, noncanonical Wnt5A/B and their receptor FZD8 were upregulated or activated by TGF- β 1 in pulmonary fibroblasts and lung tissues or CS from COPD patients, which impaired endogenous lung repair and induced inflammatory responses in COPD lung [46, 50, 53]. …”

“…In this study, the authors ascertained inflammatory cytokine releases of human lung fibroblasts, and their results showed that Wnt5B had an ability to induce CXCL8 release in MRC-5 human fibroblasts upon Wnt5A/B simulation. Equally noteworthy, Wnt5B induced more IL-6 and CXCL8 release in fibroblasts from COPD patients relative to non-COPD controls [53]. Mechanistically, these were primarily mediated by the FZD2 and TAK1 signaling and the activation of JNK, p38, and p65 NF- κ B signaling, but without an involvement of β -catenin signaling.…”

Silencing of Carbohydrate Sulfotransferase 15 Hinders Murine Pulmonary Fibrosis Development

“…CS-E was shown to act as a co-receptor for Wnt and a direct receptor for the receptor for advanced glycation end-products (RAGE) 26 . Since the activation of human lung fibroblasts including HLF cells is mediated by RAGE 27 and Wnt, 28 it is thought that CS-E activates fibroblasts at least through RAGE and/or Frizzled pathways. Interestingly, lung fibroblasts themselves express CHST15, a specific producer of CS-E. Blockade of CHST15 reduced collagen synthesis by fibroblasts, suggesting that CHST15 provides signals to synthesize collagen as well as CS-E in lung fibroblasts (Figure 2).…”

Impact of Altered WNT2B Expression on Bladder Wall Fibroblasts: Implications for Apoptosis Regulation in the Stroma of the Lower Urinary Tract

“…The rationale for this approach was results from other tissues, such as skeletal muscle, heart muscle and skin, in which WNT signalling has been described to be involved in tissue fibrosis [16-18]. There also seems to be an association of WNT signalling with transforming growth factor beta signalling [15], and in lung fibroblasts WNT5B was directly able to induce inflammatory processes [19]. Data from our own group has also shown TGF beta and WNT signalling to be altered in scar tissue from patients with vesico-urethral anastomotic stricture (VUAS) after radical prostatectomy (RP) [20].…”