Airway Epithelium: A Neglected but Crucial Cell Type in Asthma Pathobiology

Abstract

The features of allergic asthma are believed to be mediated mostly through the Th2 immune response. In this Th2-dominant concept, the airway epithelium is presented as the helpless victim of Th2 cytokines. However, this Th2-dominant concept is inadequate to fill some of the vital knowledge gaps in asthma pathogenesis, like the poor correlation between airway inflammation and airway remodeling and severe asthma endotypes, including Th2-low asthma, therapy resistance, etc. Since the discovery of type 2 innate lymphoid cells in 2010, asthma researchers started believing in that the airway epithelium played a crucial role, as alarmins, which are the inducers of ILC2, are almost exclusively secreted by the airway epithelium. This underscores the eminence of airway epithelium in asthma pathogenesis. However, the airway epithelium has a bipartite functionality in sustaining healthy lung homeostasis and asthmatic lungs. On the one hand, the airway epithelium maintains lung homeostasis against environmental irritants/pollutants with the aid of its various armamentaria, including its chemosensory apparatus and detoxification system. Alternatively, it induces an ILC2-mediated type 2 immune response through alarmins to amplify the inflammatory response. However, the available evidence indicates that restoring epithelial health may attenuate asthmatic features. Thus, we conjecture that an epithelium-driven concept in asthma pathogenesis could fill most of the gaps in current asthma knowledge, and the incorporation of epithelial-protective agents to enhance the robustness of the epithelial barrier and the combative capacity of the airway epithelium against exogenous irritants/allergens may mitigate asthma incidence and severity, resulting in better asthma control.

Keywords: airway epithelium; alarmins; allergic asthma.

Figure 1

A diagram that describes the concept changes that happened in asthma pathogenesis with time.

Figure 2

Scheme diagram to illustrate the structural changes in the airway epithelial barrier in asthmatics compared to healthy airway epithelium. When the asthmatic airway epithelium is exposed to allergens and air pollutants, it causes disruption to the tight epithelial junction and adherens junction. This leads to heightened mucosal permeability, effectuating more inhaled particles and allergens present in the subepithelial region and promoting innate and adaptive immune responses. This is accompanied by PNEC hyperplasia, a loss of ciliated cell numbers, goblet cell metaplasia, mucus hypersecretion, the thickening of the basal membrane, subepithelial fibrosis, increased airway smooth muscle mass, and the excess deposition of extracellular matrix.

Figure 3

Airway epithelia regulating epi-immune response upon allergen/pathogen exposure. Pathogens or allergens disrupt the airway epithelia. Disrupted epithelia releases alarmins (IL-25, IL-33, and TSLP). Alarmins activate dendritic cells for Th2 polarization of the immune response. On the other hand, alarmins can directly activate ILC2 cells to secret IL-4, IL-5, and IL-13 cytokines. The dysregulation of this pathway leads to asthma pathogenicity.