Smooth-muscle-derived WNT5A augments allergen-induced airway remodelling and Th2 type inflammation

Abstract

Asthma is a heterogeneous disease characterized by chronic inflammation and structural changes in the airways. The airway smooth muscle (ASM) is responsible for airway narrowing and an important source of inflammatory mediators. We and others have previously shown that WNT5A mRNA and protein expression is higher in the ASM of asthmatics compared to healthy controls. Here, we aimed to characterize the functional role of (smooth muscle-derived) WNT5A in asthma. We generated a tet-ON smooth-muscle-specific WNT5A transgenic mouse model, enabling in vivo characterization of smoothmuscle-derived WNT5A in response to ovalbumin. Smooth muscle specific WNT5A overexpression showed a clear trend towards enhanced actin (α-SMA) expression in the ASM in ovalbumin challenged animals, but had no effect on collagen content. WNT5A overexpression in ASM also significantly enhanced the production of the Th2-cytokines IL4 and IL5 in lung tissue after ovalbumin exposure. In line with this, WNT5A increased mucus production, and enhanced eosinophilic infiltration and serum IgE production in ovalbumin-treated animals. In addition, CD4 + T cells of asthma patients and healthy controls were stimulated with WNT5A and changes in gene transcription assessed by RNA-seq. WNT5A promoted expression of 234 genes in human CD4 + T cells, among which the Th2 cytokine IL31 was among the top 5 upregulated genes. IL31 was also upregulated in response to smooth muscle-specific WNT5A overexpression in the mouse. In conclusion, smooth-muscle derived WNT5A augments Th2 type inflammation and remodelling. Our findings imply a pro-inflammatory role for smooth musclederived WNT5A in asthma, resulting in increased airway wall inflammation and remodelling. Asthma is a heterogeneous disease characterized by chronic inflammation of the large and small airways. More than 200 million people worldwide are estimated to be affected by asthma 1. Asthma is characterized by episodic changes in respiratory symptoms such as breathlessness, wheezing, chest tightness and coughing, reflecting airway hyper-responsiveness (AHR). Apart from this variable component of AHR, asthma is characterized by the development of structural changes in the airways, termed airway remodelling, which contribute to airflow obstruction 2. Airway smooth muscle (ASM) is a central player in the pathology of asthma. Airway smooth muscle thickness correlates with asthma severity and lung function 3. In line with this, bronchial thermoplasty (BT) results in diminished ASM mass in severe asthmatics for up to at least two years 4 , which is associated with improvement in quality of life, and a reduction in symptoms and number of exacerbations 5. ASM cells are major

Attenuation of Expression of Splenocytes Pro-Inflammatory Cytokines and Lung Alpha-Smooth Muscle Actin By Human Amniotic Mesenchymal Stem Cells-Conditioned Medium in Asthmatic Mice

“…Additionally, it was able to suppress in ammatory cytokines like IgE, IL-4, and TGF-β, which OVA elevated, and compensate for the reduction in IFN-γ and IL-10 in splenic cells caused by OVA. Our ndings corroborated those of Koopmans et al, who demonstrated that when mice were exposed to OVA, IgE and Th2 cytokines such as IL-4 increased, and α-SMA protein expression increased in mice receiving OVA [7].…”

“…Due to hypertrophy, hyperplasia, and higher extracellular matrix protein deposition, this airway thickening exacerbates asthmatic airway constriction. Additionally, ASM is strongly associated with in ammatory cell in ltration in asthmatic patients, including lymphocytes, mast cells, and eosinophils [7]. Asthma is characterized by ASM remodeling, which involves in the expression of various proteins, including alpha-smooth muscle actin (α-SMA) protein [8].…”

PM2.5 Induces Airway Remodeling in Chronic Obstructive Pulmonary Diseases via the Wnt5a/β-Catenin Pathway

“… 14 Very recently, a study indicated that smooth muscle-derived Wnt5a induced inflammatory cytokines and the α-SMA expression in the airway smooth muscle in asthma, resulting in increased airway wall inflammation and remodeling. 35 Combined with previous reports, the relationship between the Wnt5a/β-catenin signaling pathway and PM2.5-associated airway remodeling was also established in our study.…”

WNT Signalling in Lung Physiology and Pathology

“…Mesenchymal cells exert important secretory functions with important roles in physiology and disease. The proinflammatory cytokines IL-6 and IL-8 are secreted from lung fibroblasts in a WNT-5B dependent manner through interactions with the FZD 2 and FZD 8 (van Dijk et al 2016), whereas smooth muscle derived WNT-5A contributes to Th2 cytokine production and allergic inflammation (Koopmans et al 2020). Moreover, mesenchymal cells contribute secreted growth factors such as WNTs and FGFs, which support epithelial plasticity and repair.…”