Eosinophils enhance WNT-5a and TGF-β1 genes expression in airway smooth muscle cells and promote their proliferation by increased extracellular matrix proteins production in asthma

Januškevičius, Andrius; Vaitkienė, Simona; Gosens, Reinoud; Janulaitytė, Ieva; Hoppenot, Deimantė; Sakalauskas, Raimundas; Malakauskas, Kęstutis

doi:10.1186/s12890-016-0254-9

Cited by 41 publications

(41 citation statements)

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“…Eosinophils show increased TGF-β 1 production, but are not the only source of this growth factor in the lungs, there are reports that ASM cells also produce this cytokine (Lee et al, 2006; Januskevicius et al, 2016). How eosinophils induce overexpression of TGF-β 1 via ASM cells remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The whole blood was layered on Ficoll-Paque PLUS (GE Healthcare, Finland) and centrifuged at 1000 g force for 30 min at room temperature, and then PMN were separated by hypotonic lysis of erythrocytes. Eosinophils were separated using a magnetic eosinophil isolation kit (Miltenyi Biotec, USA) according to the procedure previously described (Januskevicius et al, 2016). Manufacturer confirms that eosinophils separation kit do not influence eosinophils viability and separation efficiency are more than 97%.…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated that asthmatic eosinophils significantly enhance ASM cells proliferation comparing with healthy eosinophils and it may be related with increased eosinophils adhesion and their effect on TGF-β 1 , WNT-5a and ECM proteins production (Januskevicius et al, 2016). These findings led us to investigate possible ways how to prevent eosinophils effects on ASM remodeling in asthma.…”

Section: Introductionmentioning

confidence: 98%

“…Seven integrin heterodimers expressed by eosinophils (α 4 β 1 , α 6 β 1 , α L β 2 , α M β 2 , α X β 2 , α D β 2 , and α 4 β 7 ) mediate diverse functions, including eosinophil rolling, stable adhesion, migration, respiratory bursts, degranulation, and viability after interaction with ligands including adhesion molecules, laminin, fibrinogen/fibrin, vitronectin, and periostin on other cells or in the ECM (Barthel et al, 2008; Johansson and Mosher, 2013; Johansson et al, 2013). ASM cells express VCAM-1 and ICAM-1 adhesion molecules, which can act as ligands for eosinophils integrins α4β1 and αMβ2 and previous study revealed that the adhesion ability of eosinophils in asthma patients is significantly greater than the adhesion ability of eosinophils from healthy people (Januskevicius et al, 2016). On this basis, the potential that blocking eosinophil surface integrins as a means to suppress the impact of inflammation on airway structural cells and airway remodeling, has emerged as a potential therapeutic approach for asthma (Dekkers et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma

et al. 2017

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Background: Airway smooth muscle (ASM) remodeling is an important component of the structural changes to airways seen in asthma. Eosinophils are the prominent inflammatory cells in asthma, and there is some evidence that they contribute to ASM remodeling via released mediators and direct contact through integrin–ligand interactions. Eosinophils express several types of outer membrane integrin, which are responsible for cell–cell and cell–extracellular matrix interactions. In our previous study we demonstrated that asthmatic eosinophils show increased adhesion to ASM cells and it may be important factor contributing to ASM remodeling in asthma. According to these findings, in the present study we investigated the effects of suppression of eosinophil integrin on eosinophil-induced ASM remodeling in asthma.Materials and Methods: Individual combined cell cultures of immortalized human ASM cells and eosinophils from peripheral blood of 22 asthmatic patients and 17 healthy controls were prepared. Eosinophil adhesion was evaluated using eosinophil peroxidase activity assay. Genes expression levels in ASM cells and eosinophils were measured using quantitative real-time PCR. ASM cell proliferation was measured using alamarBlue® solution. Eosinophil integrins were blocked by incubating with Arg-Gly-Asp-Ser peptide.Results: Eosinophils from the asthma group showed increased outer membrane α4β1 and αMβ2 integrin expression, increased adhesion to ASM cells, and overexpression of TGF-β1 compared with eosinophils from the healthy control group. Blockade of eosinophil RGD-binding integrins by Arg-Gly-Asp-Ser peptide significantly reduced adhesion of eosinophils to ASM cells in both groups. Integrin-blocking decreased the effects of eosinophils on TGF-β1, WNT-5a, and extracellular matrix protein gene expression in ASM cells and ASM cell proliferation in both groups. These effects were more pronounced in the asthma group compared with the control group.Conclusion: Suppression of eosinophil-ASM interaction via RGD-binding integrins attenuates eosinophil-induced ASM remodeling in asthma.Trial Registration: ClinicalTrials.gov Identifier: NCT02648074.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma

et al. 2017

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“…In addition, the ASM is both responsive to, and produces a variety of pro-inflammatory cytokines and chemokines that are induced through para-or autocrine actions in asthma 9 . Accordingly, ASM in asthmatics closely interacts with infiltrating inflammatory cells, such as mast cells, eosinophils and lymphocytes 10,11 .…”

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confidence: 99%

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

Koopmans

Hesse

Nawijn

et al. 2020

Sci Rep

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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

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The contribution of the WNT pathway to the therapeutic effects of montelukast in experimental murine airway inflammation induced by ovalbumin and lipopolysaccharide

Kaya‐Yasar,

Engin,

Barut

et al. 2024

Drug Development Research

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The wingless/integrase‐1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic‐acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA‐Al(OH)3 administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK‐974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5‐HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5‐HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5‐HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK‐3β and WNT5A levels, which had been induced by airway inflammation, in a dose‐dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad‐2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin‐17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK‐3β phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model.

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Eosinophils enhance WNT-5a and TGF-β1 genes expression in airway smooth muscle cells and promote their proliferation by increased extracellular matrix proteins production in asthma

Cited by 41 publications

References 37 publications

Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma

Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma

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

The contribution of the WNT pathway to the therapeutic effects of montelukast in experimental murine airway inflammation induced by ovalbumin and lipopolysaccharide

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