Human airway epithelial cell innate immunity: relevance to asthma

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The innate immunity function of the human airway epithelium is responsible for orchestrating defence against inhaled viruses, bacteria, fungi, allergens, pollution, and other environmental insults. Epithelial cells present a mechanically tight, pseudostratified, multi-cell barrier that secretes mucus, surfactants, and anti-microbial peptides to manage minor insults. Secondary to the mechanical impedances, cell surface and cytoplasmic pattern recognition receptors await detection of more aggressive insults. The differentiation state of the airway epithelium contributes to innate immunity by compartmentalizing receptors and mediator production. Activation of innate immune receptors triggers production of interferons, cytokines, and chemokines, which influence adaptive immune responses. Mounting evidence suggests that these responses are aberrant in asthma and may contribute to disease progression and exacerbations. In this review, we discuss the recent evidence supporting these statements, focusing primarily on data generated from using human samples.

Highlights

► The airway epithelium is an integral component of the innate immune system. ► Airway epithelial cells detect environmental insults and initiate immune responses. ► Airway epithelium innate immune responses may influence allergic diseases. ► Airway epithelium innate immune responses are compromised in asthmatics.

Introduction

The airway epithelium is a pseudostratified mucosal barrier, consisting of multiple cell types sitting at the interface between external environment and internal milieu of the lung [1, 2] (Figure 1). In a healthy state, the airway epithelium has three main functions: (i) a tight mechanical barrier that undergoes rapid and orderly regeneration upon insult, (ii) innate immune mediator production that limits foreign antigen invasion, and (iii) chemokine/cytokine production to recruit inflammatory cells for resolution of immune responses. In asthma, the epithelial barrier is compromised and fails to properly repair, has deviations in immune mediator production, resulting in inappropriate recruitment and skewing of downstream adaptive immune responses. The focus of this review is on recent studies evaluating innate immune signaling profiles of human primary airway epithelial cells (HAECs) derived from non-asthmatics and asthmatics [3], and where possible how the differentiation status of HAECs influences these responses. Several excellent recent reviews have comprehensively covered the relationship between HAECs and dendritic cells [4, 5], and the use and applicability of animal models [6, 7, 8] and as such will not be addressed herein.

Section snippets

Antiviral and antimicrobial responses of HAECs

Antiviral innate immune signaling pathways are crucial for HAECs to respond to inhaled respiratory viruses such human rhinovirus (HRV), influenza, and respiratory syncytial virus (RSV) (Figure 2) [9, 10].

Seminal studies exploring the response of epithelium to HRV16 and HRV1b infection demonstrated that cells isolated from asthmatics in submerged monolayer culture conditions showed deficient induction of interferon-λ’s by HRV in HAECs from asthmatics, which was highly correlated with severity of

HAEC generated IL-1 family cytokines

The molecular mechanisms governing the production of the IL-1 family of cytokines has been reviewed in detail [36] and has provided a foundation to explore these cytokines in HAECs. To date 11 members of the IL-1 family have been described and include ligands and receptor inhibitors [36] with most attention given to IL-1α, IL-1β, IL-18, and IL-33. Despite the selectivity of past research, a recent screening of HAECs for the newly recognized members of IL-1 family (IL-1F5-11) identified that

Influence of HAEC innate immune responses on Th2 adaptive immune responses

The contribution of TSLP to Th2-immune skewing of adaptive immune responses in humans is well known and has been recently reviewed [48]. We present the most recent human evidence that further supports HAEC production of TSLP and other cytokines capable of contributing to Th2 adaptive immune responses.

The mechanisms by which primary HAECs produce TSLP were explored in the context of Th2 cytokines, IL-4 and IL-13, and TLR3 ligands, dsRNA and HRV16 [49]. TLR3 ligands and Th2 cytokines

Influence of Th2 adaptive immune responses on HAEC innate immune responses

Th2 skewed immune responses in the airway environment can influence HAEC function and help co-ordinate feedback loops between recruited inflammatory cells [54]. IL-4 and IL-13 signaling in HAECs requires the presence of functional receptors and signaling cascades. Consistent with differentiation dependent expression of antiviral responses in HAECs, the functional consequences of IL-4 and IL-13 depend on cell phenotype. Differentiation of HAECs in ALI cultures resulted in selective expression of

Conclusions

HAECs are integral innate immune cells that orchestrate key inflammatory events following insult. The differentiation state of HAECs can vary in disease, contributing to undesired immune events. Greater understanding of HAEC innate immune responses in disease states, reinforced with matching in situ analysis of human airway epithelium, will provide insight into the role these pathways play in health and disease.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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