NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells

Jing, Yaxun; Gimenes-Júnior, João Antonio; Mishra, Rahul; Pham, Duc Hung; Comstock, Adam T.; Yu, Daohai; Sajjan, Umadevi

doi:10.1136/thoraxjnl-2017-210593

Cited by 43 publications

(71 citation statements)

References 42 publications

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“…191 Subsequent studies demonstrated that goblet cell gene expression was reduced following treatment with a gamma-secretase inhibitor (GSK L685,458) to limit NOTCH activation. 192 Further, supplementation of feed with quercetin reduced RVinduced lung inflammation (including neutrophilia), goblet cell metaplasia, and AHR. 193…”

Section: Mouse Asthma Exacerbation Modelsmentioning

confidence: 97%

In vivo experimental models of infection and disease

Girkin

Maltby

Singanayagam

et al. 2019

Rhinovirus Infections

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Section: Mouse Asthma Exacerbation Modelsmentioning

confidence: 97%

In vivo experimental models of infection and disease

Girkin

Maltby

Singanayagam

et al. 2019

Rhinovirus Infections

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“…inhibitor had no effect on RV-induction of MUC5AC and concluded that EGFR does not play a role in promoting virus-induced mucin expression in COPD 36 . However, in this study, the authors examined mucin expression solely at a late timepoint (15 days) post RV infection and did not evaluate effects of the treatment on mucin expression at earlier timepoints nor subsequent effects on production of inflammatory mediators.…”

Section: Et Al Recently Reported In Copd Airway Epithelial Cell Cultumentioning

confidence: 98%

MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation

Singanayagam

Footitt

et al. 2019

Preprint

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The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus that is rich in mucin glycoproteins. Disrupted mucus production is a cardinal feature of chronic respiratory diseases but how this alteration affect interactions between mucins and pathogens is complex and poorly understood. Here, we identify a central and unexpected role for the major airway mucin MUC5AC in pathogenesis of virus-induced exacerbations of chronic obstructive pulmonary disease (COPD). Virus induction of MUC5AC is augmented in COPD compared to healthy subjects, is enhanced in frequent exacerbators and correlates with inflammation, symptom severity and secondary bacterial infection during exacerbation. MUC5AC is functionally related to inflammation as MUC5ACdeficient (Muc5ac-/-) mice had attenuated rhinovirus-induced airway inflammation whilst exogenous MUC5AC glycoprotein administration augmented virus-induced inflammatory responses and bacterial load. Mechanistically, MUC5AC-augmentation of rhinovirus-induced inflammation occurred through release of extracellular adenosine triphosphate (ATP). Therapeutic suppression of virus-induced MUC5AC release using an epidermal growth factor receptor (EGFR) inhibitor ameliorated exaggerated pro-inflammatory responses in a mouse COPD exacerbation model. Collectively, these studies demonstrate previously unrecognised pro-inflammatory effects of MUC5AC during infection and thus highlight a key unforeseen role in driving COPD exacerbation severity.author/funder. All rights reserved. No reuse allowed without permission.

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“…Based on this knowledge, further studies are warranted to evaluate if cigarette smoke induced oxidative stress in the airway epithelium leads to impairment of lysosome-dependent NOTCH3 protein degradation.Despite the knowledge that NOTCH3 signaling plays an important role in regulating airway epithelial differentiation(12,14,17,32), the downstream signaling events and specific targets are largely unknown. Our demonstration that over-expression of NICD3 leads to increased expression of the goblet cell promoting transcription factor SPDEF(30) in HBECs, suggests that NOTCH3 regulates goblet cell differentiation at least in part via SPDEF-dependent mechanisms.…”

mentioning

confidence: 99%

Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells

Bodas

Moore

Bharathiraja

et al. 2020

Preprint

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Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States and is primarily caused by cigarette smoking. Increased numbers of mucus-producing secretory (goblet) cells defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. Primary human bronchial epithelial cells (HBECs) from nonsmokers and COPD smokers were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using (1) the NOTCH/γ-secretase inhibitor Dibenzazepine (DBZ), (2) lentiviral over-expression of the NOTCH3-intracellular domain (NICD3) or (3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by qPCR, Western blotting, immunostaining and RNA-Seq. We found that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Over-expression of NICD3 increased the expression of goblet cell associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a novel potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

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NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells

Abstract: RV induces sustained GCH via NOTCH3 particularly in COPD cells or mice with COPD phenotype. This may be one of the mechanisms that may contribute to RV-induced prolonged airways obstruction in COPD.

Cited by 43 publications

References 42 publications

In vivo experimental models of infection and disease

In vivo experimental models of infection and disease

MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation

Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells

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