Glucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets

doi:10.1016/j.jaci.2007.10.041

Journal of Allergy and Clinical Immunology

Volume 120, Issue 6, December 2007, Pages 1247-1263

https://doi.org/10.1016/j.jaci.2007.10.041 Get rights and content

Research on the biology of airway epithelium in the last decades has progressively uncovered the many roles of this cell type during the immune response. Far from the early view of the epithelial layer simply as a passive barrier, the airway epithelium is now considered a central player in mucosal immunity, providing innate mechanisms of first-line host defense as well as facilitating adaptive immune responses. Alterations of the epithelial phenotype are primarily involved in the pathogenesis of allergic airways disease, particularly in severe asthma. Appreciation of the epithelium as target of glucocorticoid therapy has also grown, because of studies defining the pathways and mediators affected by glucocorticoids, and studies illustrating the relevance of the control of the response from epithelium in the overall efficacy of topical and systemic therapy with glucocorticoids. Studies of the mechanism of action of glucocorticoids within the biology of the immune response of the epithelium have uncovered mechanisms of gene regulation involving both transcriptional and posttranscriptional events. The view of epithelium as therapeutic target therefore has plenty of room to evolve, as new knowledge on the role of epithelium in immunity is established and novel pathways mediating glucocorticoid regulation are elucidated.

Section snippets

Epithelial responses in allergic airways and in the anti-inflammatory action of glucocorticoid

The airway epithelium is a multifunctional, highly organized cellular layer separating the host tissue from the atmosphere. It provides many crucial homeostatic respiratory functions, such as gas and fluid transport, oxidant defense, mucociliary clearance, and innate antimicrobial defense. At the same time, it is able to respond to either external factors brought by inhalation, such as viruses, pollutants, and allergens, or to molecular signals from neighboring or infiltrating cells, such as

Action of glucocorticoids on the different epithelial phenotypes

In nondiseased state, the respiratory epithelium is composed of cellular components of different origin and phenotypes, whose discrete roles integrate in performing homeostatic and inducible functions. Embryologically, the airway epithelium derives from the endodermal layer of the embryo; histologically, it presents in the upper airways as a pseudostratified columnar layer containing basal, ciliated, and mucus-producing goblet cells, transitioning in the bronchioli into a cuboidal, single cell

Effect of glucocorticoids on mucus production and airway mucociliary clearance

Together with the cough reflex, mucociliary clearance (MCC) is an essential nonspecific mechanism of defense of the airways that is carried out by the ciliated cells and by goblet cells. Evaluation of bronchial specimens from asthmatic deaths⁴⁷ as well as bronchial biopsies from moderate and mild asthma⁴⁸ shows that the epithelial cell types involved in this function display various degrees of damage. Besides the alterations of ciliated cells,³⁰ there is hyperplasia of goblet cell as well as of

Effects of glucocorticoid on epithelial innate immune responses

Standing at the edge of the respiratory tree and facing the outside world, epithelial cells are the prime protagonist of the innate immune surveillance in the airways. Once past the mucus barrier, a large host of innate antimicrobial responses are carried by epithelial cells on cell activation mediated by transmembrane and cytoplasmic PRRs, belonging to either TLR and non-TLR families, or other entry receptors recognizing a wide spectrum of microbial components and proteins, named collectively

Effects of glucocorticoids on epithelial functions involved in adaptive immune responses

After the triggering of a direct, innate immune response, pathogen recognition elicits a shift toward higher adaptive immune responses, and epithelial cells actively participate in this process. In response to PRR engagement, epithelial cells secrete factors that recruit and activate dendritic cells (DCs) as well as leukocytes, serving as an essential bridge between innate and adaptive responses; subsequently, the epithelium is able to respond to the cytokine milieu established by the recruited

Integrated mechanisms of action for a multitasking hormone

Glucocorticoids exert their anti-inflammatory action through a global, integrated action on the mechanisms that regulate gene expression, from early signaling events to the nuclear, transcriptional mechanisms and to posttranscriptional and posttranslational regulatory events occurring mainly in the cytoplasm. The study of glucocorticoid action in genome-wide studies has clearly shown that the net result of this complex regulation, which acts in a highly context-specific, cell-specific, and

Summary

Glucocorticoids exert a profound effect on the immune functions performed by epithelial cells in innate and adaptive immunity. It is now well established by studies in vitro and in vivo that glucocorticoids provide a substantial inhibition of the proinflammatory response mounted by the epithelium in response to triggers produced by inflammatory cells, and that the control of this epithelial-driven response is an important component of the efficacy of glucocorticoid therapy in asthma and other

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The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19.
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Lung inflammation may lead to excessive fluid accumulation in the airways which can reduce gas exchange and mucociliary clearance. Pulmonary oedema and flooding of the airways are hallmarks of severe COVID-19 lung disease. The volume of airway surface liquid is determined by a delicate balance of salt and water secretion and absorption across the airway epithelium. In addition to its anti-inflammatory actions, dexamethasone modulates the activity of ion channels which regulate electrolyte and water transport across the airway epithelium. The observations of dexamethasone activation of sodium ion absorption via ENaC Na⁺ channels and inhibition of chloride ion secretion via CFTR Cl⁻ channels to decrease airway surface liquid volume indicate a novel therapeutic action of the glucocorticoid to reverse airway flooding.
This brief review delves into the early non-genomic and late genomic signaling mechanisms of dexamethasone regulation of ion channels and airway surface liquid dynamics, shedding light on the molecular mechanisms underpinning the action of the glucocorticoid in managing COVID-19.
Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes
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Citation Excerpt :
Though regulation by GCs/GR has been extensively studied on the transcriptional level, the impact of GCs on post-transcriptional gene regulatory mechanisms is largely unknown, with the exception of a small subset of pro-inflammatory genes. These include effector molecules such as Tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), and Chemokine (CC motif) ligands (CCL)2 and CCL7, suggesting a role for GCs/GR in post-transcriptional gene expression modulation [15–18]. In the present study, we aimed at systematically investigating the global impact of Dex treatment on the transcriptional and post-transcriptional regulation of gene expression in an inflammatory setting.
Glucocorticoids such as dexamethasone (Dex) are widely used to treat both acute and chronic inflammatory conditions. They regulate immune responses by dampening cell-mediated immunity in a glucocorticoid receptor (GR)-dependent manner, by suppressing the expression of pro-inflammatory cytokines and chemokines and by stimulating the expression of anti-inflammatory mediators. Despite its evident clinical benefit, the mechanistic underpinnings of the gene regulatory networks transcriptionally controlled by GR in a context-specific manner remain mysterious. Next generation sequencing methods such mRNA sequencing (RNA-seq) and Ribosome profiling (ribo-seq) provide tools to investigate the transcriptional and post-transcriptional mechanisms that govern gene expression. Here, we integrate matched RNA-seq data with ribo-seq data from human acute monocytic leukemia (THP-1) cells treated with the TLR4 ligand lipopolysaccharide (LPS) and with Dex, to investigate the global transcriptional and translational regulation (translational efficiency, ΔTE) of Dex-responsive genes. We find that the expression of most of the Dex-responsive genes are regulated at both the transcriptional and the post-transcriptional level, with the transcriptional changes intensified on the translational level. Overrepresentation pathway analysis combined with STRING protein network analysis and manual functional exploration, identified these genes to encode immune effectors and immunomodulators that contribute to macrophage-mediated immunity and to the maintenance of macrophage-mediated immune homeostasis. Further research into the translational regulatory network underlying the GR anti-inflammatory response could pave the way for the development of novel immunomodulatory therapeutic regimens with fewer undesirable side effects.
Effect of long-term oral corticosteroid therapy in severe T2-weighted asthma patients
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L’asthme est sévère lorsqu’il ne peut être contrôlé par des traitements inhalés à dose maximale (à condition qu’ils soient pris bien entendu), alors que la prise en charge des comorbidités et des autres facteurs précipitants ou aggravants ait été optimisée. Cette forme d’asthme ne concerne qu’environ 5 % des asthmatiques mais représente environ 60 % des dépenses.
Les corticostéroïdes ont révolutionné la prise en charge de l’asthme, confirmant la nature inflammatoire de cette maladie. L’identification des mécanismes d’action des corticoïdes dans cette maladie a permis de définir l’inflammation de type 2, ses acteurs clés (IL-4, IL-5, IL-13, TSLP, IL-33, IgE) et ses biomarqueurs non invasifs (éosinophiles de l’expectoration et/ou du sang et/ou tissulaires, FeNO, allergie à la fois clinique et biologique, polypose naso-sinusienne, possiblement l’intolérance aux AINS et à l’aspirine, cortico-dépendance) pour l’identifier chez les patients. On estime qu’au moins 60 à 80 % des asthmatiques ont ce profil.
Les stratégies d’épargne en corticostéroïdes oraux (CSO) suscitent un intérêt particulier en raison de leurs effets secondaires potentiels. Le recours aux CSO au-delà de 0,5 à 1 g/an expose de façon majeure aux complications des glucocorticoïdes et il s’agit d’un seuil facile à identifier pour déclencher l’adressage du patient à un centre expert de l’asthme sévère, car des solutions d’épargne cortisonique très efficaces sont maintenant disponibles.
© 2020 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés.
Severe asthma is defined by a disease that remains partially controlled, or even uncontrolled, despite high dose of inhaled corticosteroid (ICS), while the management of comorbidities and other precipitating or aggravating factors has been optimized. Severe asthma represents only 5% of the asthma population but significant economic burden is associated with the disease and represents 60% of healthcare costs. Corticosteroids have completely revolutionized the management of asthma, confirming the inflammatory nature of this disease. Identification of corticosteroids biological mechanisms in asthma allows to define type 2 inflammation, the inflammatory mediators (IL-4, IL-5, IL-13, TSLP, IL-33, IgE) and the non-invasive biomarkers (sputum and/or blood eosinophilia and/or tissue inflammation, FeNO, clinical and biological allergy, nasal polyposis, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) intolerance, corticosteroid dependent asthma). At least 60 to 80% of asthmatic patients have T2 inflammatory profile.
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© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.
ORMDL3 modulates airway epithelial cell repair in children with asthma under glucocorticoid treatment via regulating IL-33
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Study found that glucocorticoids, as first-line treatments for asthma, fails to prevent asthma recurrence. Orosomucoid-like (ORMDL) 3 is associated to childhood asthma onset and involved in the inflammation and repair of airway epithelium. We explored the functional role of ORMDL3 in glucocorticoid treatment for childhood asthma.
Mice were sensitized with Ovalbumin (OVA) and treated with Dexamethasone (Dex), followed by OVA challenge to establish a mouse model of asthma. Histopathological changes in lung tissues were observed by hematoxylin-eosin and masson staining. Human bronchial epithelial (16HBE-14°) cells were transfected with ORMDL3 overexpression plasmid and siRNA-interleukin (IL)-33 alone or in combination, followed by Dex. Cell viability was measured by MTT assay. Cell migration was evaluated by wound healing assay. The expressions of E-cadherin and Vimentin and the activation of NF-κB and MAPK/ERK in 16HBE-14° cells were assessed by Western blot. The expressions of ORMDL3 and IL-33 in lung tissues and 16HBE-14° cells were analyzed by qRT-PCR or Western blot.
Dex treatment alleviated the histopathological abnormality and reversed the overexpressions of ORMDL3 and IL-33 in the lung tissues of asthmatic mice. Overexpressed ORMDL3 enhanced migration and viability, decreased E-cadherin level, increased the levels of IL-33 and Vimentin, and promoted the phosphorylation of NF-κB and MAPK/ERK in Dex-treated 16HBE-14° cells, thus reversing the effect of Dex treatment. However, siRNA-IL-33 inhibited viability and migration, increased E-cadherin level, decreased Vimentin level, and suppressed the phosphorylation of NF-κB and MAPK/ERK, thus reversing the effect of overexpressed ORMDL3 in Dex-treated 16HBE-14° cells.
ORMDL3 overexpression helped airway epithelial cellrepairin asthma via regulating IL-33 expression.
Induction of thymic stromal lymphopoietin by a steroid alkaloid derivative in mouse keratinocytes
2018, International Immunopharmacology
Citation Excerpt :
With chemical formula of C28H45NO2 and molecular weight of 427.67, 02F04 has a similar chemical structure (shown in Fig. 1A) as oxysterols, the endogenous ligands of nuclear receptor of liver X receptor (LXR). Indeed, glucocorticoids such as dexamethasone, which has a steroidal structure, are known to inhibit TSLP production [16] and to possess strong anti-inflammatory effect through multiple mechanisms including regulation of the nuclear receptor of glucocorticoids receptor (GR) [17]. However, there are hardly any reports on steroidal compounds inducing TSLP production.
Thymic stromal lymphopoietin (TSLP) plays critical roles in inducing and exacerbating allergic diseases. Chemical compounds that induce TSLP production can enhance sensitization to antigens and exacerbate allergic inflammation. Hence, identifying such chemicals will be important to prevent an increase in allergic diseases. In the present study, we found, for the first time, that a steroid alkaloid derivative, code no. 02F04, concentration and time dependently induced mRNA expression and production of TSLP in a mouse keratinocyte cell line, PAM212. In particular, the activity of 02F04 was selective to TSLP. As an analogue of the liver X receptor (LXR) endogenous ligand, 02F04 rapidly increased ATP-binding cassette transporter A1 (ABCA1) expression by regulating the nuclear receptor of LXR. However, instead of being inhibited by the LXR antagonist, 02F04-induced TSLP production was delayed and markedly suppressed by inhibitors of phospholipase C (PLC), pan-protein kinase C (PKC), PKCδ, Rho-associated protein kinase (ROCK), extracellular signal-regulated kinase (ERK) 1/2, and IκΒ kinase 2 (IKK2). Treatment with 02F04 caused the formation of F-actin filaments surrounding the nucleus of PAM212 cells, which then disappeared following addition of ROCK inhibitor. 02F04 also induced phosphorylation of ERK1/2 from 2 h after treatment, with a maximum at 24 h, and increased nuclear factor-κB (NF-κB) promoter activity by 1.3-fold. Taken together, these results indicate that 02F04-induced TSLP production is regulated via distinct signal transduction pathways, including PLC, PKC, ROCK, ERK1/2, and NF-κB but not nuclear receptors. 02F04, with a unique skeletal structure in inducing TSLP production, can represent a potential new tool for investigating the role of TSLP in allergic diseases.
DUSP1 maintains IRF1 and leads to increased expression of IRF1-dependent genes: A mechanism promoting glucocorticoid insensitivity
2016, Journal of Biological Chemistry
Although the mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, mediates dexamethasone-induced repression of MAPKs, 14 of 46 interleukin-1β (IL1B)-induced mRNAs were significantly enhanced by DUSP1 overexpression in pulmonary A549 cells. These include the interferon regulatory factor, IRF1, and the chemokine, CXCL10. Of these, DUSP1-enhanced mRNAs, 10 including CXCL10, were IRF1-dependent. MAPK inhibitors and DUSP1 overexpression prolonged IRF1 expression by elevating transcription and increasing IRF1 mRNA and protein stability. Conversely, DUSP1 silencing increased IL1B-induced MAPK phosphorylation while significantly reducing IRF1 protein expression at 4 h. This confirms a regulatory network whereby DUSP1 switches off MAPKs to maintain IRF1 expression. There was no repression of IRF1 expression by dexamethasone in primary human bronchial epithelial cells, and in A549 cells IL1B-induced IRF1 protein was only modestly and transiently repressed. Although dexamethasone did not repress IL1B-induced IRF1 protein expression at 4–6 h, silencing of IL1B plus dexamethasone-induced DUSP1 significantly reduced IRF1 expression. IL1B-induced expression of CXCL10 was largely insensitive to dexamethasone, whereas other DUSP1-enhanced, IRF1-dependent mRNAs showed various degrees of repression. With IL1B plus dexamethasone, CXCL10 expression was also IRF1-dependent, and expression was reduced by DUSP1 silencing. Thus, IL1B plus dexamethasone-induced DUSP1 maintains expression of IRF1 and the IRF1-dependent gene, CXCL10. This is supported by chromatin immunoprecipitation showing IRF1 recruitment to be essentially unaffected by dexamethasone at the CXCL10 promoter or at the promoters of more highly repressed IRF1-dependent genes. Since IRF1-dependent genes, such as CXCL10, are central to host defense, these data may help explain the reduced effectiveness of glucocorticoids during asthma exacerbations.

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: (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

: Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

: C.S. is supported by National Institutes of Health grant R01 AI060990-01A1.

: Disclosure of potential conflict of interest: The author has declared that she has no conflict of interest.

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Reviews and feature articlesGlucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets

Section snippets

Epithelial responses in allergic airways and in the anti-inflammatory action of glucocorticoid

Action of glucocorticoids on the different epithelial phenotypes

Effect of glucocorticoids on mucus production and airway mucociliary clearance

Effects of glucocorticoid on epithelial innate immune responses

Effects of glucocorticoids on epithelial functions involved in adaptive immune responses

Integrated mechanisms of action for a multitasking hormone

Summary

Trends Immunol

Chest

Chest

Mol Immunol

J Allergy Clin Immunol

Tissue Cell

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Br J Dis Chest

J Allergy Clin Immunol

Chest

Trends Pharmacol Sci

J Biol Chem

Steroids

Pulm Pharmacol Ther

Curr Opin Pharmacol

Blood

Blood

J Biol Chem

J Biol Chem

Mol Cell Endocrinol

J Allergy Clin Immunol

The airway epithelium: structural and functional properties in health and disease

Respirology

Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm

Physiol Rev

Severe asthma is an epithelial disease

Eur Respir J

The immunogenetics of asthma and eczema: a new focus on the epithelium

Nat Rev Immunol

Mechanisms of glucocorticosteroid action

Glucocorticoids suppress inflammation but spare innate immune responses in airway epithelium

Proc Am Thorac Soc

Glucocorticoids enhance or spare innate immunity: effects in airway epithelium are mediated by CCAAT/enhancer binding proteins

J Immunol

Cellular and molecular characteristics of basal cells in airway epithelium

Exp Lung Res

Increased expression of p21(waf) cyclin-dependent kinase inhibitor in asthmatic bronchial epithelium

Am J Respir Cell Mol Biol

The effect of respiratory synctial virus on chemokine release by differentiated airway epithelium

Exp Lung Res

Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion

Am J Respir Cell Mol Biol

Induced trefoil factor family 1 expression by trans-differentiating Clara cells in a murine asthma model

Am J Respir Cell Mol Biol

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

Am J Physiol Lung Cell Mol Physiol

Dexamethasone alters bronchoalveolar lavage fluid proteome in a mouse asthma model

Int Arch Allergy Immunol

Regulation of surfactant protein D in human fetal lung

Am J Respir Cell Mol Biol

Number and proliferation of neuroendocrine cells in normal human airway epithelium

Am J Respir Crit Care Med

Functional morphology of pulmonary neuroepithelial bodies: extremely complex airway receptors

Anat Rec A Discov Mol Cell Evol Biol

Immunomodulatory functions of the diffuse neuroendocrine system: implications for bronchopulmonary dysplasia

Endocr Pathol

Increased numbers of neuroepithelial bodies (NEB) in lungs of fetal rhesus monkeys following maternal dexamethasone treatment

Cell Tissue Res

Differential regulation of calcitonin secretion in normal and neoplastic pulmonary neuroendocrine cells in vitro

Exp Lung Res

Airway mucosal inflammation even in patients with newly diagnosed asthma

Am Rev Respir Dis

Apoptosis and loss of adhesion of bronchial epithelial cells in asthma

Int Arch Allergy Immunol

Ciliated cell damage in the bronchial epithelium of asthmatics and non-asthmatics

Clin Exp Allergy

Asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis

Am J Respir Cell Mol Biol

Reviews and feature articles
Glucocorticoid actions on airway epithelial responses in immunity: Functional outcomes and molecular targets