Prostanoid Receptors of the EP<sub>4</sub>-Subtype Mediate Gene Expression Changes in Human Airway Epithelial Cells with Potential Anti-Inflammatory Activity

Joshi, Radhika; Hamed, Omar; Dong, Yan; Michi, Aubrey N.; Mostafa, Mahmoud; Wiehler, Shahina; Newton, Robert; Giembycz, Mark A.

doi:10.1124/jpet.120.000196

Cited by 9 publications

(4 citation statements)

References 98 publications

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“…To examine the effects of PGE 2 on respiratory epithelial function, we cultured healthy human tracheal and sinus epithelium in the presence or absence of PGE 2 . Of the 4 PGE 2 receptors (EP1–4), EP4 and to a lesser extent EP2 are expressed in airway epithelial cells ( 26 ). We found that chronic exposure to PGE 2 progressively increased 3D organoid diameter in an EP4- but not EP2-dependent fashion ( Figure 5, A and B ), similar to effects reported in intestinal epithelium ( 27 , 28 ).…”

Section: Resultsmentioning

confidence: 99%

IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

Kotas¹,

Moore²,

Gurrola³

et al. 2022

JCI Insight

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Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E 2 (PGE 2 ) concentration. Allergic airway epithelia bore a signature of PGE 2 activation, and PGE 2 activation led to cystic fibrosis transmembrane receptor–dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

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Section: Resultsmentioning

confidence: 99%

IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

Kotas¹,

Moore²,

Gurrola³

et al. 2022

JCI Insight

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“…To examine the effects of PGE2 on respiratory epithelial function, we cultured healthy human tracheal and sinus epithelium in the presence or absence of PGE2. Of the four PGE2 receptors (EP1-4), EP4 and to a lesser extent EP2 are expressed in airway epithelial cells (26). We found that chronic exposure to PGE2 progressively increased 3D organoid diameter in an EP4- but not EP2-dependent fashion (Figure 5A-B), similar to effects reported in intestinal epithelium (27, 28).…”

Section: Resultsmentioning

confidence: 99%

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

Kotas

Moore

Gurrola

et al. 2022

Preprint

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Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single cell RNA sequencing of airway epithelium and mouse modeling, we find that IL-13 expands and programs airway tuft cells towards eicosanoid metabolism, and that tuft cell deficiency leads to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bear a signature of prostaglandin E2 activation, and PGE2 activation leads to CFTR-dependent ion and fluid secretion and accelerated mucociliary transport. Together these data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

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“…A cAMP-dependent mechanism was also implied in BEAS-2B cells treated with the selective EP2and EP4-receptor agonists ONO-AE1-259 and ONO-AE1-329, respectively (Suzawa et al, 2000). These ligands promote canonical, cAMP-dependent signaling in human airway epithelial cells but are partial agonists (Joshi et al, 2021) and were, therefore, used in cells pre-treated with the PDE4 inhibitor, RNO (1 µM). Exposure of BEAS-2B cells to ONO-AE1-259 and ONO-AE1-329 (both 1 µM; 60 min) reduced basal pERK1/2 levels, which was blocked by the EP2and EP4-receptor antagonists TG4-155 (Jiang et al, 2012) and L-161,982 (Machwate et al, 2001), respectively (both 1 µM; 30 min pre-treatment) (Fig.…”

Section: β2-adrenoceptor Agonists Promoted Erk1/2 Dephosphorylation In Airway Epithelial Cells Bymentioning

confidence: 99%

“…They also posit that this "biased agonism" is mediated by β2-adrenoceptors located on airway epithelial cells. This is a credible proposal because the airway epithelium promotes and regulates inflammatory processes, is the first site of action for inhaled therapies and expresses a population of efficiently coupled β2-adrenoceptors (Davis et al, 1990;Joshi et al, 2021;Kelsen et al, 1995;Knight and Holgate, 2003;Penn et al, 1994). Moreover, extracellular signal-regulated kinases 1 and 2 (ERK1/2) are phosphorylated to a greater degree in bronchial biopsies taken from asthmatic subjects than in healthy controls, with changes in the airway epithelium being positively correlated with indices of inflammation (Alam and Gorska, 2011;Liu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

β₂-Adrenoceptor Agonists Promote Extracellular Signal-Regulated Kinase 1/2 Dephosphorylation in Human Airway Epithelial Cells by Canonical, cAMP-Driven Signaling Independently of β-Arrestin 2

et al. 2021

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Chronic use of β2-adrenoceptor agonists as a monotherapy in asthma is associated with a loss of disease control and an increased risk of mortality. Herein, we tested the hypothesis that β2adrenoceptor agonists, including formoterol, promote biased, β-arrestin 2 (βArr2)-dependent activation of the mitogen-activated protein (MAP) kinases, ERK1/2, in human airway epithelial cells and, thereby, effect changes in gene expression that could contribute to their adverse clinical outcomes. Three airway epithelial cell models were used: the BEAS-2B cell line, human primary bronchial epithelial cells (HBEC) grown in submersion culture and HBEC that were highly differentiated at an air-liquid interface. Unexpectedly, treatment of all epithelial cell models with formoterol decreased basal ERK1/2 phosphorylation. This was mediated by cAMP-dependent protein kinase and involved the inactivation of C-rapidly-activated fibrosarcoma, which attenuated down-stream ERK1/2 activity, and the induction of dual-specificity phosphatase-1. Formoterol also inhibited the basal expression of early growth response-1, an ERK1/2-regulated gene that controls cell growth and repair in the airways. Neither carvedilol, a β2-adrenoceptor agonist biased towards βArr2, nor formoterol promoted ERK1/2 phosphorylation in BEAS-2B cells although β2-adrenoceptor desensitization was compromised in ARRB2-deficient cells. Collectively, these results contest the hypothesis that formoterol activates ERK1/2 in airway epithelia by nucleating a βArr2 signaling complex; instead, they indicate that β2adrenoceptor agonists inhibit constitutive ERK1/2 activity in a cAMP-dependent manner. These findings are the antithesis of results obtained using acutely challenged native and engineered HEK293 cells, which have been used extensively to study mechanisms of ERK1/2 activation, and highlight the cell-type-dependence of β2-adrenoceptor-mediated signaling. SIGNIFICANCE STATEMENTIt has been proposed that the adverse-effects of β2-adrenoceptor agonist monotherapy in asthma are mediated by genomic mechanisms that occur principally in airway epithelial cells and are the result of β-arrestin 2-dependent activation of ERK1/2. This study shows that β2-adrenoceptor agonists, paradoxically, reduced ERK1/2 phosphorylation in airway epithelia by disrupting upstream Ras-C-Raf complex formation and inducing DUSP1. Moreover, these effects were PKA-dependent suggesting that β2-adrenoceptor agonists were not biased toward β-arrestin 2 and acted via canonical, cAMPdependent signaling.

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Prostanoid Receptors of the EP₄-Subtype Mediate Gene Expression Changes in Human Airway Epithelial Cells with Potential Anti-Inflammatory Activity

Abstract: Running Head: Genomic effects of an EP 4-receptor agonist in human airway epithelia

Cited by 9 publications

References 98 publications

IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

β₂-Adrenoceptor Agonists Promote Extracellular Signal-Regulated Kinase 1/2 Dephosphorylation in Human Airway Epithelial Cells by Canonical, cAMP-Driven Signaling Independently of β-Arrestin 2

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Prostanoid Receptors of the EP4-Subtype Mediate Gene Expression Changes in Human Airway Epithelial Cells with Potential Anti-Inflammatory Activity

Abstract: Running Head: Genomic effects of an EP 4-receptor agonist in human airway epithelia

Cited by 9 publications

References 98 publications

IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

β2-Adrenoceptor Agonists Promote Extracellular Signal-Regulated Kinase 1/2 Dephosphorylation in Human Airway Epithelial Cells by Canonical, cAMP-Driven Signaling Independently of β-Arrestin 2

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Prostanoid Receptors of the EP₄-Subtype Mediate Gene Expression Changes in Human Airway Epithelial Cells with Potential Anti-Inflammatory Activity

β₂-Adrenoceptor Agonists Promote Extracellular Signal-Regulated Kinase 1/2 Dephosphorylation in Human Airway Epithelial Cells by Canonical, cAMP-Driven Signaling Independently of β-Arrestin 2