Airway epithelial regulation of allergic sensitization in asthma

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Abstract

While many of the contributing cell types and mediators of allergic asthma are known, less well understood are the factors that influence the development of allergic responses that lead to the development of allergic asthma. As the first airway cell type to respond to inhaled factors, the epithelium orchestrates downstream interactions between dendritic cells (DCs) and CD4+ T cells that quantitatively and qualitatively dictate the degree and type of the allergic asthma phenotype, making the epithelium of critical importance for the genesis of allergies that later manifest in allergic asthma. Amongst the molecular processes of critical importance in airway epithelium is the transcription factor, nuclear factor-kappaB (NF-κB). This review will focus primarily on the genesis of pulmonary allergies and the participation of airway epithelial NF-κB activation therein, using examples from our own work on nitrogen dioxide (NO2) exposure and genetic modulation of airway epithelial NF-κB activation. In addition, the mechanisms through which Serum Amyloid A (SAA), an NF-κB-regulated, epithelial-derived mediator, influences allergic sensitization and asthma severity will be presented. Knowledge of the molecular and cellular processes regulating allergic sensitization in the airways has the potential to provide powerful insight into the pathogenesis of allergy, as well as targets for the prevention and treatment of asthma.

Introduction

Afflicting greater than 34 million Americans [1] and costing over 18 billion dollars annually [2], allergic asthma is a primary public health concern. The incidence of asthma has been rising steadily in the United States over the past two decades [3] and there are many potential reasons for this increase. Allergic asthma is the result of an inappropriate adaptive immune response to an inhaled antigen and is typically characterized by airway inflammation with eosinophils and lymphocytes, increased levels of Th2 cytokines, circulating IgE, airway goblet (mucus-producing) cell metaplasia, and airway hyperreponsiveness (bronchoconstriction in response to inhalation of a specific (allergen) or non-specific (methacholine, cold air) agonist) [4]. The immune response in allergic asthma is driven primarily by CD4+ T helper type 2 (Th2) lymphocytes [4], activation of which is both necessary [5] and sufficient [6] to induce all of the features of allergic asthma in mice. Th17 cells producing IL-17A, IL-17F, and IL-22 are pathogenic in severe asthma involving neutrophilia [7] and a steroid-unresponsive form of the disease [8]. Despite knowing much about effector mechanisms in allergic asthma that promote airway hyperresponsiveness, eosinophilia or neutrophilia, IgE, and mucus production, still poorly understood are the mechanisms that allow for initial allergen sensitization. Allergic sensitization, the act or process of inducing an acquired allergy, requires activation of antigen-presenting cells, such as dendritic cells [9] that induce the expansion of naïve CD4+ T cells [10] and influence their differentiation into Th2 or Th17 effectors. Importantly, pulmonary epithelium can direct the activities of dendritic cells and, thereby, affect CD4+ T cell activities that are critical for qualitatively shaping the type of allergic response manifest upon subsequent encounter with inhaled antigens. Especially important in airway epithelium is the transcription factor, NF-κB, which we have reported substantially influences the development of allergic asthma during both allergen challenge and during allergen sensitization (Fig. 1).

Section snippets

Nitrogen dioxide and allergic asthma

Nitrogen dioxide (NO2) is a free-radical gaseous [11] component of indoor and outdoor air pollution generated during combustion processes, such as the operation of motor vehicles and biomass burning [12], [13], [14]. In humans, NO2 can cause acute lung injury [15] and trigger asthma exacerbations, particularly in children [14], [16], [17], [18], [19], [20], [21]. Concentrations of NO2 above 5ppm cause lung damage [22], [23], whereas lower concentrations (100–400 ppb) contribute to poor

Nitrogen dioxide-promoted allergic sensitization

It remains incompletely understood how and why in an otherwise healthy lung, a cascade of events is initiated to allow innocuous inhaled antigens to initiate an allergic reaction that can manifest in the pathophysiological features of allergic asthma upon subsequent antigen exposure. We developed a mouse model of NO2 exposure followed by inhalation of ovalbumin to study mechanistically the effects of NO2 on allergic sensitization. We have reported that NO2 acts as an adjuvant, promoting the

Airway epithelium in allergic sensitization

As the first line of defense against inhaled insult, the airway epithelium participates both in maintaining barrier function and initiating innate immune responses. Epithelial cells express cell-surface and intracellular pattern recognition receptors that enable them to detect microbial infection, danger (such as by inhaled oxidant gasses and respirable particulate matter), and cellular damage to synthesize pro-inflammatory cytokines that recruit and/or activate other innate and adaptive immune

Airway epithelial NF-κB: providing transcriptional control of allergic sensitization

Of the many signaling cascades activated by airway epithelium in response to stimulation, nuclear factor-kappaB (NF-κB) family members are critical regulators of innate and adaptive immunity. NF-κB is activated by cytokines, mitogens, physical and oxidative stress, infection, and microbial products [71]. The canonical and non-canonical NF-κB cascades are initiated by upstream kinases, IkappaB kinases (IKK), which are inducibly phosphorylated by kinases further upstream, including the IL-1

Serum amyloid A (SAA) as an inflammatory mediator

Acute phase responses are induced in an attempt to eliminate pathogens, alter host metabolism, and transition between innate and adaptive immunity. SAA is an acute phase protein that is upregulated over 1000-fold in response to infection, exposure to microbes and microbial products such as LPS, inflammatory cytokines, glucocorticoids, and SAA itself [89], [90]. Of relevance to the lung, SAA has been reported as a biomarker for a causal mediator in sarcoidosis [91], COPD [92], [93], and asthma

IL-17 in severe allergic asthma

IL-17 is elevated in the lungs, BAL fluid, sputum, and serum of asthmatics [111], [112], wherein the levels positively correlate with disease severity, including the magnitude of airway hyperresponsiveness [113], [114], [115], [116] and neutrophilia [117]. In mouse models, inhalation-mediated allergen sensitization is associated with the generation of Th17 cells [40], [118], which are sufficient to drive neutrophilic airway inflammation, AHR, and glucocorticoid-resistant disease – all

Epithelial-derived SAA in the origin and exacerbation of severe allergic asthma

Since short-term exposure to NO2 or NF-κB activation in airway epithelial cells induces acute neutrophilia [27], which has been associated with the induction of an acute phase response [89], we measured expression of Saa3, the SAA inducibly expressed in mouse lungs [137], following exposure to 15ppm of NO2 for 1 h. The Saa3 increases we have reported [90] were reflected by elevated SAA protein expression localized to the airway epithelium (Fig. 2) in response to NO2. We corroborated the

Summary

The complex interplay between airway epithelium and pulmonary leukocytes modulates allergic sensitization that predisposes to the development of allergic asthma. Therefore, a better understanding of the sequence of events leading to allergic sensitization, the involvement of resident and inflammatory cells, and the interactions that lead to airway epithelial NF-κB activation and mediator secretion, as well as complementary pathways in epithelial and other lung cells, may provide crucial

Acknowledgments

MEP is supported by grants R01 HL089177, R01 HL107291, P20 RR15557, and P20 RR 021905 from the National Institutes of Health, as well as a Clinical Innovator award from the Flight Attendant Medical Research Institute (FAMRI). MEP thanks Jennifer L. Ather for her extensive research contribution frequently cited in this article.

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