Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients

Abstract

The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell-surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation.

Keywords: Asthma; cytokine; homeostasis; innate immunity; tight junction.

Fig 1

A, Schematic representation of a pseudostratified bronchial epithelial cell layer (comprising a goblet cell, 2 ciliated cells, and 2 basal cells) showing the junctional complexes and their interactions with the cytoskeleton or basement membrane to form a robust sheet-like structure. B, Illustration of the TJ and AJ complexes showing how they mediate cell-cell contact and interact with the actin cytoskeleton. ECM, Extracellular matrix; JAM, junctional adhesion molecule; ZO, zonula occludens.

Fig 2

Schematic representation of epithelial barrier function illustrating protective and immunoregulatory functions. Under basal conditions, the epithelium maintains homeostasis by limiting exposure of the airway tissue to components of the inhaled environment and by balancing immunoregulatory signals. However, when compromised, the epithelium responds by releasing innate cytokines that help to orchestrate appropriate innate and adaptive immune responses. CS, Cigarette smoke; NO_x, nitrogen oxides; O^·, oxygen radicals; PM, particulate matter; Treg, regulatory T cell.

Fig 3

Schematic representation of the epithelial barrier in asthmatic patients highlighting abnormalities in protective and immunoregulatory functions (gray boxes). Persistent airway inflammation most likely arises as a consequence of impaired barrier defenses (altered cytoprotective secretions and reduced cell-cell adhesion), leading to epithelial susceptibility to injury and dysregulated immune responses. In parallel, impaired repair might contribute to maintenance of epithelial activation and chronicity of responses. The relative contribution of each aspect of barrier dysfunction is likely to influence the overall phenotype of the epithelium and might manifest as distinct subgroups of asthma. CS, Cigarette smoke; NO_x, nitrogen oxides; O^·, oxygen radicals; PM, particulate matter.

Fig 4

Pictorial representation of the SCs and GCs found in a transcriptomic analysis of epithelial brushings from 155 donors. Red indicates high, pink indicates medium, and blue indicates low expression of genes within the cluster. The bar chart indicates the percentage of healthy control subjects and patients with mild, moderate, or severe asthma in each SC, and the width of the bar is proportional to the number of subjects in the cluster. Findings are summarized from Modena et al.

Fig 5

Potential mechanisms of asthma defined by epithelial barrier dysfunction. Identification of potential links with asthma susceptibility genes and their interaction with environmental stimuli are shown.