WDPCP Modulates Cilia Beating Through the MAPK/ERK Pathway in Chronic Rhinosinusitis With Nasal Polyps

Cilia loss and dysfunction is one of the typical pathological features of chronic rhinosinusitis with nasal polyps (CRSwNP). Tryptophan-aspartic acid (W-D) repeat containing planar cell polarity effector (WDPCP) has been proven to be an essential element for ciliogenesis in human nasal epithelium, but its role in the beating of cilia remains unclear. In this study, we sought to investigate the role of WDPCP and its underlying mechanism behind the dysfunction in the beating of cilia in nasal polyp tissue. We demonstrated WDPCP expression in the epithelium of nasal polyps. We also investigated the MAPK/ERK pathway in primary human sinonasal epithelial cells to explore the function of WDPCP. The air–liquid interface culture system was used as a model to verify the role of WDPCP and the MAPK/ERK pathway in the beating of cilia. With the dysfunction of cilia beating, we observed a low expression of WDPCP in the epithelium of nasal polyp tissues. Within the in vitro study, we found that WDPCP was critical for mitochondrial biogenesis and mitochondrial function in human sinonasal epithelial cells, possibly due to the activation of the MAPK/ERK pathway. The mitochondrial dysfunction caused by U0126 or lacking WDPCP could be partially recovered by dexamethasone. The low expression of WDPCP in nasal epithelium could affect mitochondria via the MAPK/ERK pathway, which may contribute to the dysfunction in the beating of cilia in CRSwNP.

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WDPCP modulates cilia beating through MAPK/ERK pathway in chronic rhinosinusitis

10.21203/rs.3.rs-22917/v1 ◽

2020 ◽

Author(s):

Yun Ma ◽

Peng Tian ◽

Hua Zhong ◽

Fan Wu ◽

Qining Zhang ◽

...

Keyword(s):

Epithelial Cells ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Planar Cell Polarity ◽

Essential Element ◽

Nasal Epithelium ◽

Erk Pathway ◽

Low Expression

Abstract Background: Cilia loss and dysfunction is one of the typical pathological features of chronic rhinosinusitis. Tryptophan-aspartic acid (W-D) repeat containing planar cell polarity effector (WDPCP) has been proven to be an essential element for ciliogenesis in human nasal epithelium, but its role in the beating of cilia remains unclear. Cilia beating requires energy from the mitochondria, which is regulated by the MAPK/ERK pathway. In this study, we sought to investigate the role of WDPCP and its underlying mechanism behind the dysfunction in the beating of cilia in chronic rhinosinusitis.Methods: We demonstrated WDPCP expression in the epithelium of nasal polyps. We also investigated the MAPK/ERK pathway in primary human sinonasal epithelial cells to explore the function of WDPCP. The air-liquid interface culture system was used as a model to verify the role of WDPCP and the MAPK/ERK pathway in the beating of cilia.Results: With the dysfunction of cilia beating, we observed a low expression of WDPCP in the epithelium of nasal polyps. Within the in vitro study, we found that WDPCP was critical for mitochondrial biogenesis and mitochondrial function in human sinonasal epithelial cells, possibly due to the activation of the MAPK/ERK pathway. The mitochondrial dysfunction caused by U0126 or lacking WDPCP could be partially recovered by dexamethasone.Conclusion: The low expression of WDPCP in nasal epithelium could affect mitochondria via the MAPK/ERK pathway, which may contribute to the dysfunction in the beating of cilia in chronic rhinosinusitis.

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Involvement of the Extracellular Matrix Proteins Periostin and Tenascin C in Nasal Polyp Remodeling by Regulating the Expression of MMPs

10.21203/rs.3.rs-118180/v1 ◽

2020 ◽

Author(s):

Kun Du ◽

Min Wang ◽

Nan Zhang ◽

Ping Wang ◽

Pei Yu ◽

...

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Chronic Rhinosinusitis ◽

Nasal Polyp ◽

Nasal Polyps ◽

Ex Vivo ◽

Tissue Remodeling ◽

Tenascin C ◽

Protein Levels ◽

Control Subjects

Abstract Background: Tissue remodeling caused by increased MMPs is involved in the pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP). We previously found higher levels of periostin and tenascin C in CRSwNPs, but whether they are associated with the dysregulation of MMPs is unknown. Therefore, the present study aimed to investigate the regulatory roles of two ECM proteins in the expression of MMPs in nasal polyps.Methods：The concentrations of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, TIMP-1, TIMP-2, TIMP-3, TIMP-4, periostin, and tenascin C in tissue homogenates of 51 patients with chronic rhinosinusitis with and without nasal polyps and 15 control subjects were measured and their correlations were analyzed. Primary human nasal polyp fibroblasts and epithelial cells were stimulated ex vivo with periostin and tenascin C and the gene expression of MMPs and TIMPs was determined by means of real-time PCR.Results: The protein levels of MMP-3, MMP-7, MMP-8, MMP-9, TIMP-1, TIMP-2, periostin, and tenascin C were significantly higher in patients with CRSwNPs than in healthy control subjects. Periostin was positively correlated with MMP-3 and TIMP-2, and tenascin C was positively correlated with MMP-3, MMP-7, MMP-8, MMP-9 and TIMP-2. Periostin stimulated the gene expression of MMP-3, MMP-7, and MMP-9 in fibroblasts and MMP-7 in epithelial cells ex vivo. Tenascin C stimulated the expression of MMP-3, MMP-8, and MMP-9 in epithelial cells, but not in fibroblasts. The expression of TIMPs in fibroblasts and epithelial cells was affected by neither periostin nor tenascin C. Conclusions：Periostin and tenascin C might be involved in the remodeling of nasal polyps by regulating the expression of different MMPs in epithelial cells and fibroblasts. Our findings have the potential to identify key factors of tissue remodeling in CRSwNPs.

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Role of cAMP-PKA/CREB pathway in regulation of AQP 5 production in rat nasal epithelium

Rhinology Journal ◽

10.4193/rhino10.107 ◽

2011 ◽

Vol 49 (4) ◽

pp. 464-469

Author(s):

W. Wang ◽

M. Zheng

Keyword(s):

Epithelial Cells ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Nasal Epithelium ◽

Aquaporin 5 ◽

Nasal Epithelial Cells ◽

Aqp5 Protein ◽

Creb Pathway

OBJECTIVES: Aquaporin 5 (AQP5) is a water-specific channel protein. In this study, we investigated the possible role of the cyclic adenosine monophosphate-protein kinase A/cyclic adenosine monophosphate response element binding protein (cAMP-PKA/CREB) pathway in the regulation of AQP5 in nasal epithelial cells. METHODS: Rat nasal epithelial cells were cultured and treated with the PKA inhibitor H89 or cAMP inducing medicine forskolin for 12 or 24 hours in vitro. AQP5 and phosphorylated CREB (p-CREB) at serine133 (Ser133) were detected by immunocytochemistry, Western blotting or real-time PCR. Experiments were repeated 10 times. RESULTS: After treatment with H89 for 12 or 24 hours, the number of cells positive for AQP5 and p-CREB (Ser133) were decreased, p-CREB (Ser133) and AQP5 protein decreased, and AQP5 mRNA decreased. After treatment with forskolin for 12 or 24 hours, the number of p-CREB (Ser133) and AQP5 positive cells increased, p-CREB (Ser133) and AQP5 protein increased, and AQP5 mRNA was increased. CONCLUSION: Both H89 (PKA inhibitor) and forskolin (cAMP inducing medicine) regulate AQP5 production through the cAMP-PKA/CREB pathway, which could influence the secretory function of the submucosal glands in nasal epithelium.

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Characterization of the Eosinophil Chemokine Rantes in Nasal Polyps

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348949810700510 ◽

1998 ◽

Vol 107 (5) ◽

pp. 416-420 ◽

Cited By ~ 28

Author(s):

Jerilyn S. Allen ◽

Roselle Eisma ◽

Gerald Leonard ◽

Denis Lafreniere ◽

Donald Kreutzer

Keyword(s):

Epithelial Cells ◽

Nasal Polyp ◽

Total Protein ◽

Nasal Polyps ◽

Nasal Polyposis ◽

Enzyme Linked Immunosorbent Assay ◽

Eosinophil Recruitment ◽

Tissue Homogenates ◽

Immunohistochemical Techniques

Previous studies have demonstrated that the cytokine RANTES (Regulated And Normal T cell Expressed and Secreted) has been shown to be a potent mediator of eosinophil Chemotaxis in vitro and of leukocyte recruitment. Because eosinophils are the hallmark cells in nasal polyposis, we hypothesize that RANTES is locally produced within the nasal polyp microenvironment and is responsible for the eosinophil recruitment seen in nasal polyposis. To begin to test this hypothesis, we evaluated nasal polyps from 17 patients and 3 control specimens for distribution and content of RANTES using immunohistochemical techniques and enzyme-linked immunosorbent assay technology. Our immunohistochemical studies demonstrated that in nasal polyposis, RANTES antigen staining occurred predominantly within eosinophils and epithelial cells. To quantify the relative levels of RANTES in normal and nasal polyp specimens, tissue homogenates were prepared, quantified, and normalized to protein levels. We detected RANTES in all 17 nasal polyp tissue homogenates (566 ± 16 pg/mg total protein). The RANTES levels in nasal polyp homogenates were nearly 40-fold higher man the RANTES levels in normal tissue (15.7 ± 28.2 pg/mg total protein). Thus, it appears that increased expression of RANTES by eosinophils and epithelial cells within the nasal polyp microenvironment promotes eosinophil recruitment and activation within nasal polyps. We hypothesize that RANTES induces increased recruitment and activation of eosinophils, presumably contributing to the increased tissue changes associated with nasal polyposis.

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Cytokine Signature and Involvement in Chronic Rhinosinusitis with Nasal Polyps

International Journal of Molecular Sciences ◽

10.3390/ijms23010417 ◽

2021 ◽

Vol 23 (1) ◽

pp. 417

Author(s):

Florent Carsuzaa ◽

Émilie Béquignon ◽

Xavier Dufour ◽

Guillaume de Bonnecaze ◽

Jean-Claude Lecron ◽

...

Keyword(s):

Epithelial Cells ◽

Inflammatory Response ◽

Chronic Rhinosinusitis ◽

Inflammatory Cytokines ◽

Nasal Polyps ◽

Inflammatory Cells ◽

Eosinophilic Infiltration ◽

Th2 Cytokines ◽

Current State

Cytokines are well known to play a central role in chronic rhinosinusitis with nasal polyps (CRSwNP), particularly in maintenance of the inflammatory response and the recruitment of eosinophils. The pathophysiological concepts concerning the involvement of inflammatory cytokines in CRSwNP have gradually evolved. Although the Th2 cytokines environment associated with an eosinophilic infiltration has retained a central role in the genesis of polyps, the role of other cytokine subpopulations has also and more recently been detailed, leading to a specific and complex signature in CRSwNP. The purpose of this review is to summarize the current state of knowledge about the cytokine signature in CRSwNP, the role of cytokines in the pathogenesis of this disease and in the intercellular dialog between epithelial cells, fibroblasts and inflammatory cells. Knowledge of this precise cytokine signature in CRSwNP is fundamental in the perspective of potential targeting biotherapies.

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