Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice

Fong, Valerie; Hsu, Austin; Xie, Tian; Looney, Agnieszka; Ganesan, Previn; Ren, Xin; Sheppard, Dean; Wicher, S.A.; Thompson, Michael A.; Britt, Rodney D.; Prakash, Y. S.; Bhattacharya, Mallar

doi:10.1172/jci.insight.123578

Cited by 9 publications

(13 citation statements)

References 30 publications

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“…This study was conducted on an RNA-Seq dataset from human ASM cells (NCBI GEO GSE119578). The experimental design, sample collection, and library preparation for RNA-Seq are previously reported 88 . For human samples, written informed consent was obtained from all subjects, and the study was approved by the Mayo Clinic Institutional Review Board.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were grown in DMEM/F12 media supplemented with 10% fetal bovine serum (FBS) and 1% antibiotic/antimycotic (AbAm). After the cells reached 80% confluency, they were serum-starved with DMEM/F12 media (without FBS) and 1% AbAm for 48 h. RNA isolation was performed from cell lysates at Mayo clinic, as reported elsewhere 88 . After RNA quality control, RNA libraries were prepared using 200 ng total RNA per the manufacturer’s instructions for TruSeq RNA Sample Prep Kit v2 (Illumina).…”

Section: Methodsmentioning

confidence: 99%

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Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma

Banerjee

Balraj

Ambhore

et al. 2021

Sci Rep

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Airway smooth muscle (ASM) is known for its role in asthma exacerbations characterized by acute bronchoconstriction and remodeling. The molecular mechanisms underlying multiple gene interactions regulating gene expression in asthma remain elusive. Herein, we explored the regulatory relationship between ASM genes to uncover the putative mechanism underlying asthma in humans. To this end, the gene expression from human ASM was measured with RNA-Seq in non-asthmatic and asthmatic groups. The gene network for the asthmatic and non-asthmatic group was constructed by prioritizing differentially expressed genes (DEGs) (121) and transcription factors (TFs) (116). Furthermore, we identified differentially connected or co-expressed genes in each group. The asthmatic group showed a loss of gene connectivity due to the rewiring of major regulators. Notably, TFs such as ZNF792, SMAD1, and SMAD7 were differentially correlated in the asthmatic ASM. Additionally, the DEGs, TFs, and differentially connected genes over-represented in the pathways involved with herpes simplex virus infection, Hippo and TGF-β signaling, adherens junctions, gap junctions, and ferroptosis. The rewiring of major regulators unveiled in this study likely modulates the expression of gene-targets as an adaptive response to asthma. These multiple gene interactions pointed out novel targets and pathways for asthma exacerbations.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma

Banerjee

Balraj

Ambhore

et al. 2021

Sci Rep

Self Cite

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“…Studies with Rho‐kinase inhibitor, Y‐27632, showed that Y‐27632 can relax the isolated human bronchial preparation and inhibit the increased airway resistance 55‐57 . Very impressively, the bronchodilatory effect of inhaled Y‐27632 starts promptly and lasts over 8 h 58,59 . Recently, Fong et al 59 firstly reported that ARHGEF12 was the most highly expressed RhoGEF in the airway smooth muscle of asthmatic patients and in the lung tissues of house dust mite (HDM)‐induced mouse model of asthma.…”

Section: Rhoa/rho‐kinase and Airway Hyper‐responsivenessmentioning

confidence: 99%

“…Very impressively, the bronchodilatory effect of inhaled Y‐27632 starts promptly and lasts over 8 h 58,59 . Recently, Fong et al 59 firstly reported that ARHGEF12 was the most highly expressed RhoGEF in the airway smooth muscle of asthmatic patients and in the lung tissues of house dust mite (HDM)‐induced mouse model of asthma. The ARHGEF12‐deficient mice showed significantly decreased AHR relative to wild‐type mice 59 .…”

Section: Rhoa/rho‐kinase and Airway Hyper‐responsivenessmentioning

confidence: 99%

“…Recently, Fong et al 59 firstly reported that ARHGEF12 was the most highly expressed RhoGEF in the airway smooth muscle of asthmatic patients and in the lung tissues of house dust mite (HDM)‐induced mouse model of asthma. The ARHGEF12‐deficient mice showed significantly decreased AHR relative to wild‐type mice 59 . ARHGEF1, another RhoGEF, is an activator of RhoA increased in the airway smooth muscles from patients with asthma and in the lung tissues from OVA‐challenged mice 61 .…”

Section: Rhoa/rho‐kinase and Airway Hyper‐responsivenessmentioning

confidence: 99%

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RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

et al. 2020

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Asthma is a chronic and heterogeneous disease characterised by airway inflammation and intermittent airway narrowing. The key obstacle in the prevention and treatment of asthma has been our incomplete understanding of its aetiology and biological mechanisms. The ras homolog family member A (RhoA) of the Rho family GTPases has been considered to be one of the most promising and novel therapeutic targets for asthma. It is well known that RhoA/Rho-kinases play an important role in the pathophysiology of asthma, including airway smooth muscle contraction, airway hyper-responsiveness, b-adrenergic desensitisation and airway remodelling. However, recent advances have suggested novel roles for RhoA in regulating allergic airway inflammation. Specifically, RhoA has been shown to regulate allergic airway inflammation through controlling Th2 or Th17 cell differentiation and to regulate airway remodelling through regulating mesenchymal stem cell (MSC) differentiation. In this review, we evaluate the literature regarding the recent advances in the activation of RhoA/Rho-kinase, cytokine and epigenetic regulation of RhoA/Rho-kinase, and the role of RhoA/Rho-kinase in regulating major features of asthma, such as airway hyperresponsiveness, remodelling and inflammation. We also discuss the importance of the newly identified role of RhoA/Rho-kinase signalling in MSC differentiation and bronchial epithelial barrier dysfunction. These findings indicate the functional significance of the RhoA/Rho-kinase pathway in the pathophysiology of asthma and suggest that RhoA/Rho-kinase signalling may be a promising therapeutic target for the treatment of asthma.

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Fasudil and SR1001 synergistically protect against sepsis-associated pancreatic injury by inhibiting RhoA/ROCK pathway and Th17/IL-17 response

Liu,

Xiao,

et al. 2023

Heliyon

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Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice

Cited by 9 publications

References 30 publications

Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma

Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma

RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

Fasudil and SR1001 synergistically protect against sepsis-associated pancreatic injury by inhibiting RhoA/ROCK pathway and Th17/IL-17 response

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