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
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
References (176)
The epithelium takes centre stage in asthma and atopic dermatitis
Trends Immunol
(2007)- et al.
The effect of inflammation on mucociliary clearance in asthma: an overview
Chest
(2000) Goblet cell and mucin gene abnormalities in asthma
Chest
(2002)- et al.
The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity
Mol Immunol
(2005) - et al.
Histopathologic features of early and progressive asthma
J Allergy Clin Immunol
(2000) - et al.
Attachment of columnar airway epithelial cells in asthma
Tissue Cell
(2005) - et al.
Proliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthma
J Allergy Clin Immunol
(2001) - et al.
Airways remodeling is a distinctive feature of asthma and is related to severity of disease
Chest
(1997) - et al.
A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial
J Allergy Clin Immunol
(1992) - et al.
Changes in sputum counts and airway hyperresponsiveness after budesonide: monitoring anti-inflammatory response on the basis of surrogate markers of airway inflammation
J Allergy Clin Immunol
(2002)
Bronchial ciliogenesis and oral steroid treatment in patients with asthma
Br J Dis Chest
Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression
J Allergy Clin Immunol
Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack
Chest
Anti-inflammatory actions of steroids: molecular mechanisms
Trends Pharmacol Sci
hCLCA1 and mCLCA3 are secreted non-integral membrane proteins and therefore are not ion channels
J Biol Chem
Rapid anti-secretory effects of glucocorticoids in human airway epithelium
Steroids
Inhibition of eosinophil transepithelial migration and downregulation of adhesion molecule expression on eosinophils and airway epithelial cells induced by budesonide
Pulm Pharmacol Ther
Viral-associated exacerbations of asthma and COPD
Curr Opin Pharmacol
Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes
Blood
Glucocorticoids in innate immunity: more transactivation than transrepression!
Blood
Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2
J Biol Chem
Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase
J Biol Chem
Glucocorticoids and the innate immune system: crosstalk with the Toll-like receptor signaling network
Mol Cell Endocrinol
Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment
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
Cited by (46)
Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes
2022, Computational and Structural Biotechnology JournalCitation 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.
Effect of long-term oral corticosteroid therapy in severe T2-weighted asthma patients
2020, Revue des Maladies Respiratoires ActualitesORMDL3 modulates airway epithelial cell repair in children with asthma under glucocorticoid treatment via regulating IL-33
2020, Pulmonary Pharmacology and TherapeuticsInduction of thymic stromal lymphopoietin by a steroid alkaloid derivative in mouse keratinocytes
2018, International ImmunopharmacologyCitation 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.
DUSP1 maintains IRF1 and leads to increased expression of IRF1-dependent genes: A mechanism promoting glucocorticoid insensitivity
2016, Journal of Biological Chemistry
(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.