Role of Respiratory Epithelial Cells in Allergic Diseases

Abstract

The airway epithelium provides the first line of defense to the surrounding environment. However, dysfunctions of this physical barrier are frequently observed in allergic diseases, which are tightly connected with pro- or anti-inflammatory processes. When the epithelial cells are confronted with allergens or pathogens, specific response mechanisms are set in motion, which in homeostasis, lead to the elimination of the invaders and leave permanent traces on the respiratory epithelium. However, allergens can also cause damage in the sensitized organism, which can be ascribed to the excessive immune reactions. The tight interaction of epithelial cells of the upper and lower airways with local and systemic immune cells can leave an imprint that may mirror the pathophysiology. The interaction with effector T cells, along with the macrophages, play an important role in this response, as reflected in the gene expression profiles (transcriptomes) of the epithelial cells, as well as in the secretory pattern (secretomes). Further, the storage of information from past exposures as memories within discrete cell types may allow a tissue to inform and fundamentally alter its future responses. Recently, several lines of evidence have highlighted the contributions from myeloid cells, lymphoid cells, stromal cells, mast cells, and epithelial cells to the emerging concepts of inflammatory memory and trained immunity.

Keywords: airway lining fluids; airways; allergy; asthma; epithelial immunity.

Figure 1

Schematic overview on biomarkers involved in immunological processes of the epithelial airway barrier. The airway lumen unifies cytokines and mediators of different origins, from immune cells as well as the airway epithelium. While cytokines produced by immune cells transmigrate through the epithelial barrier and can be detected indirectly, mediators produced and secreted by airway epithelial cells have a more direct access. However, epithelium-derived mediators can be secreted on the apical surface, as well on the basal layer. Airway epithelial cells are pre-committed to a type 2 (E2) or type 1 (E1) like phenotype, resulting from a priming effect of airway epithelial cells, which was named after the causative Th1 versus Th2-derived cytokines. E2 epithelial cell activation by allergens takes place and their pro-inflammatory cytokines and chemokines induce inflammation, contributing to an epithelial type 2 response, the so called “E2 response,” with epithelial alarmins TSLP, IL-31, CCL-26, IL-25, and IL-33. Immune cell-derived type 2 responses involve multiple cytokines, including IL-4, IL-5, IL-9, IL-13, IL-33, and increased eosinophil numbers. Bronchial hyperreactivity takes place, leading to an enhanced susceptibility to bronchoconstriction mediated by, e.g., IL-13. E1 epithelial cells arise as a response to, e.g., viral infections secreting CXCL2, CXCL8, IL12, CCL2, and CCL20, thus stimulating the local synthesis of IFN-γ, IL-2, IL-12, IL-18, IL-36, and TNF-a that present a wide range of antiviral activities, inducing the upregulation of MHC-I molecules and antiviral resistance in uninfected cells. Neutrophils respond to the infection signals IL-12 and IFN-γ by releasing pro-inflammatory cytokines, which leads to the limitation of the infection, rise of body temperature, and to the recruitment of further phagocytic cells. Upon allergen exposure, airway epithelial cells are activated by a variety of receptors, releasing chemoattractant mediators and recruiting a variety of immune cells to the airways, leading to an increased mast cell-derived release of IL-13 and TNF, which play a crucial role in inducing the mucus production by goblet cells.