Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation

Abstract

Airway epithelial cells form a barrier to the outside world and are at the front line of mucosal immunity. Epithelial apical junctional complexes are multiprotein subunits that promote cell-cell adhesion and barrier integrity. Recent studies in the skin and gastrointestinal tract suggest that disruption of cell-cell junctions is required to initiate epithelial immune responses, but how this applies to mucosal immunity in the lung is not clear. Increasing evidence indicates that defective epithelial barrier function is a feature of airway inflammation in asthmatic patients. One challenge in this area is that barrier function and junctional integrity are difficult to study in the intact lung, but innovative approaches should provide new knowledge in this area in the near future. In this article we review the structure and function of epithelial apical junctional complexes, emphasizing how regulation of the epithelial barrier affects innate and adaptive immunity. We discuss why defective epithelial barrier function might be linked to TH2 polarization in asthmatic patients and propose a rheostat model of barrier dysfunction that implicates the size of inhaled allergen particles as an important factor influencing adaptive immunity.

Keywords: Airway epithelium; adherens junction; allergy; asthma; barrier defect; innate immunity; mucosal immunity; tight junction.

Figure 1

Cartoon diagram of airway epithelial cells indicating junctional structures including tight junctions (black) and adherens junctions (blue), which are intimately linked with perijunctional actin filaments. The inset shows an enlarged schematic of protein-protein interactions in tight junctions (black text) and adherens junctions (blue text), including ability of ZO proteins to interact with intracytoplasmic domains. The inset also indicates that junctional proteins are linked to the actin cytoskeleton (green dashed line) via several potential adaptor proteins (black dashed line). Inhaled allergens, air pollutants, and respiratory viruses can cause to dysfunction of epithelial junction resulting in greater outside/in permeability (see text, and Table 2). Barrier dysfunction can lead to epithelial cell signaling or differentiated, since it will allow apical growth factors constitutively present in epithelial lining fluids (red dots) to interact with their basolateral receptors. In the presence of intact epithelial junctions, these ligand/receptor interactions are prevented. Barrier dysfunction will also allow greater sampling of luminal allergens (blue stars) by intra-epithelial dendritic cells (DC), including CD103+ DC which interdigitate in the epithelium. Allergen-induced Th2 responses can induce a vicious cycle of leak, since Th2 cytokines perpetuate junctional dysfunction (see text and Table 3). Another consequence of leaky epithelial barriers is increased microbial invasion (green oval), which might predispose susceptible asthmatics to exacerbations or lung infections.

Figure 2

Rheostat model of airway epithelial barrier function. At steady-state (far right), airway epithelial cells normally exclude particles greater than ~30-50 nM in diameter. In the presence of dysfunctional barriers, progressively larger particles will traverse apical junctions (right to left). Barrier dysfunction likely facilitates sampling of luminal contents by DC dendrites (not shown), thus promoting the outside/in translocation of inhaled allergen particles that deposit on the cell surface. In addition to surface properties, the size of inhaled allergen particles might influence their uptake by intra-epithelial DC subsets, which in turn could influence quality and intensity of subsequent adaptive immune responses. The possibility that sustained and persistent barrier disruption leads to reparative responses or increased regulatory tone is indicated on the far left.