CTNNAL1 participates in the regulation of mucus overproduction in HDM‐induced asthma mouse model through the YAP‐ROCK2 pathway

Wu, Danping; Wang, Jiang; Liu, Caixia; Liu, Lexin; Li, Furong; Ma, Xiaodi; Pan, Lang; Liu, Chi; Qu, Xiangping; Liu, Huijun; Qin, Xiaoqun; Xiang, Yang

doi:10.1111/jcmm.17206

Cited by 12 publications

(14 citation statements)

References 54 publications

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“…The respiratory virus infection further exacerbates the asthmatic condition, resulting in hypersecretion of airway mucus, obstructing the airway, and increasing airway resistance. Our simultaneous assessment of inflammatory factors and airway resistance in lung tissue and alveolar lavage fluid showed that respiratory viral infection also exacerbated lung inflammation and increased airway resistance in asthmatic mice by a mechanism that, in addition to being associated with the YAP/FOXM1 pathway, YAP can also exacerbate lung tissue by regulating other pathways, such as NF-κB [44,45] and YAP/ROCK2 [46] inflammatory response. Lung inflammation, goblet cell hyperplasia, and mucus hypersecretion induce asthma attacks.…”

Section: Discussionmentioning

confidence: 88%

Poly(I:C) Exacerbates Airway Goblet Cell Hyperplasia and Lung Inflammation in HDM-Exposed Balb/C Mice by YAP/FOXM1 Pathway

Feng

et al. 2023

Int Arch Allergy Immunol

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Introduction: Respiratory viral infection in childhood is closely associated with asthmatic attacks. Of all predisposing factors, viral infection is the primary contributor to acute childhood asthma exacerbations. However, the mechanisms involved in viral asthma are unclear. This study attempted to provide insights into molecular mechanisms in respiratory virus-induced acute asthma exacerbations. Methods: House dust mite (HDM) was given by intranasal administration to induce asthma in mice. Poly(I:C) was used to mimic the viral infection. A selective YAP inhibitor, verteporfin (VP), was used to investigate the role of the YAP/FOXM1 pathway. The expression of YAP, FOXM1, cytokines, and inflammatory cells in lung tissue, and bronchoalveolar lavage fluid (BALF) was determined using RT-PCR, immunohistochemical, ELISA, and flow cytometry studies. The methacholine challenge assesses airway hyperresponsiveness. In 16HBE cell experiments, we selectively inhibited YAP and FOXM1 by VP and RCM1, respectively, and detected the expression of YAP and FOXM1. Results: The experimental studies have confirmed the YAP/FOXM1 pathway plays a vital role in the differentiation and proliferation of airway club cells into goblet cells and lung inflammation. Poly(I:C) upregulated the expression of FOXM1 by activating transcription factor YAP in mice airway epithelial cells and then promoted the expression of downstream transcription factors SPDEF/MUC5AC, resulting in airway mucus hypersecretion and hyperresponsiveness. In addition, Poly(I:C) facilitates the expression of inflammatory factors in lung tissue. All of these events induce asthma exacerbations. The in vitro studies have confirmed that YAP positively regulates FOXM1 in airway epithelial cells. Conclusion: Poly(I:C) promotes airway epithelial goblet cell hyperplasia, mucus hypersecretion, and airway hyperresponsiveness. It also upregulates the expression of inflammatory factors in lung tissue and BALF in asthmatic mice by the YAP/FOXM1 pathway, resulting in asthma attacks.

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Section: Discussionmentioning

confidence: 88%

Poly(I:C) Exacerbates Airway Goblet Cell Hyperplasia and Lung Inflammation in HDM-Exposed Balb/C Mice by YAP/FOXM1 Pathway

Feng

et al. 2023

Int Arch Allergy Immunol

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“…CTNNAL1 was found to be ubiquitously expressed in many tissues, including skeletal muscle, the pancreas, and the heart 31 . By comparing psoriasis patients who did not have psoriatic arthritis and patients with psoriatic arthritis, Patrick MT et al identi ed signi cant loci overlapping the regulatory elements that encompass genes that are differentially expressed in differentiated osteoblasts, including genes that participate in Wnt signaling, such as RUNX1, FUT8, and CTNNAL1 32 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide association study identiﬁes new susceptibility genes and pathways for spondyloarthritis

Chen

Teng

et al. 2022

Preprint

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Background: Spondyloarthritis (SpA) is a group of multifactorial bone diseases influenced by genetic factors, the environment and lifestyle. However, current studies have found a limited number of SpA-related genes, and the genetic and pathogenic mechanism of SpA is still unclear. Methods: A tissue-specific transcriptome-wide association study (TWAS) of SpA was performed by using genome-wide association study (GWAS, including 3966 SpA patients and 452264 controls) summary data and gene expression weights of whole blood and skeletal muscle. The SpA-associated genes identified by TWAS were further compared with the differentially expressed genes (DEGs) identified in the SpA gene expression profile acquired from the Gene Expression Omnibus database (GEO, GSE58667). Finally, FUMA and Metascape were used to perform functional enrichment and annotation analysis.Results: The TWAS detected 28 significant genes associated with SpA in whole blood and skeletal muscle, such as CTNNAL1 (PSM=0.0304, PWB=0.0096). The gene expression profile of SpA identified 20 candidate genes that overlapped in the TWAS data, such as MCM4 (PTWAS=0.0132, PDEG=0.0275) and KIAA1109 (PTWAS=0.0371, PDEG =0.0467). Enrichment analysis of the genes identified by TWAS identified 93 significant GO terms 33 and KEGG pathways, such as mitochondrion organization (GO:0007005) and axon guidance (hsa04360).Conclusion: We identified multiple candidate genes that were genetically related to SpA. Our study may provide novel clues of the genetic mechanism, diagnosis, and treatment of SpA.

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“…MUC5AC and mucin5B (MUC5B) are integral components of airway mucus [18] . In our previous study, we demonstrated that CTNNAL1 deficiency results in an increase in MUC5AC secretion but does not influence MUC5B expression [11] . CFTR is an apical membrane chloride channel critical to the regulation of fluid, chloride, and bicarbonate transport in epithelial and other cell types [19] .…”

Section: Introductionmentioning

confidence: 89%

“…There is a negative correlation between the reduction in CTNNAL1 expression and airway hyperresponsiveness [10] . CTNNAL1 deficiency enhances lung inflammation and mucus hypersecretion through activation of the YAP-ROCK2 signaling pathway [11] .…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown that ROCK1 and ROCK2 have functional overlaps in some cases; however, they cannot be replaced by each other [ 14 , 16 , 17 ]. Our previous study demonstrated that ROCK1 expression decreases but ROCK2 expression increases in the lungs of a CTNNAL1 -silenced mouse model and that CTNNAL1 deficiency increases mucin5AC (MUC5AC) secretion through the ROCK2 signaling pathway [11] . However, it is unknown whether CTNNAL1 regulates the expression of cystic fibrosis transmembrane conductance regulator (CFTR) through the Rho/ROCK signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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CTNNAL1 deficiency suppresses CFTR expression in HDM-induced asthma mouse model through ROCK1-CAL signaling pathway

Wu¹,

Zhu²,

Yang³

et al. 2023

ABBS

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The downregulation of adhesion molecule catenin alpha-like 1 (CTNNAL1) in airway epithelial cells of asthma patients and house dust mite (HDM)-induced asthma animal models was illustrated in our previous study. It is assumed to contribute to airway inflammation and mucus hypersecretion. In this work, we further explore the underlying mechanism of CTNNAL1 in asthma. CTNNAL1 -silenced female mice exhibit a decreased level of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated and ATP-gated Cl – channel that correlates with mucus hypersecretion. Our previous study demonstrated that ROCK1 expression decreases but ROCK2 expression increases in the lungs of a CTNNAL1 -silenced mouse model. Inhibition of ROCK1 leads to a reduction in CFTR expression in CTNNAL1-overexpressing and CTNNAL1 -silenced human bronchial epithelial (HBE) cells. It has been reported that ROCK1 is a downstream target of RhoA and that activation of RhoA increases CFTR expression after CTNNAL1 deficiency in vitro and in vivo . The above results indicate that CTNNAL1 regulates CFTR expression through the ROCK1 pathway. In addition, the expression of CFTR-associated ligand (CAL) is increased after CTNNAL1 silencing, and immunoprecipitation results confirm the interaction between ROCK1 and CAL. Inhibition of CAL does not influence ROCK1 expression but increases CFTR expression in CTNNAL1 -silenced HBE cells. These data suggest that CTNNAL1 deficiency decreases CFTR expression in the HDM-induced asthma mouse model through the ROCK1-CAL signaling pathway.

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CTNNAL1 participates in the regulation of mucus overproduction in HDM‐induced asthma mouse model through the YAP‐ROCK2 pathway

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 12 publications

References 54 publications

Poly(I:C) Exacerbates Airway Goblet Cell Hyperplasia and Lung Inflammation in HDM-Exposed Balb/C Mice by YAP/FOXM1 Pathway

Poly(I:C) Exacerbates Airway Goblet Cell Hyperplasia and Lung Inflammation in HDM-Exposed Balb/C Mice by YAP/FOXM1 Pathway

Transcriptome-wide association study identiﬁes new susceptibility genes and pathways for spondyloarthritis

CTNNAL1 deficiency suppresses CFTR expression in HDM-induced asthma mouse model through ROCK1-CAL signaling pathway

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