More Than Just a Barrier: The Immune Functions of the Airway Epithelium in Asthma Pathogenesis

Abstract

Allergic bronchial asthma is a chronic disease of the airways that is characterized by symptoms like respiratory distress, chest tightness, wheezing, productive cough, and acute episodes of broncho-obstruction. This symptom-complex arises on the basis of chronic allergic inflammation of the airway wall. Consequently, the airway epithelium is central to the pathogenesis of this disease, because its multiple abilities directly have an impact on the inflammatory response and thus the formation of the disease. In turn, its structure and functions are markedly impaired by the inflammation. Hence, the airway epithelium represents a sealed, self-cleaning barrier, that prohibits penetration of inhaled allergens, pathogens, and other noxious agents into the body. This barrier is covered with mucus that further contains antimicrobial peptides and antibodies that are either produced or specifically transported by the airway epithelium in order to trap these particles and to remove them from the body by a process called mucociliary clearance. Once this first line of defense of the lung is overcome, airway epithelial cells are the first cells to get in contact with pathogens, to be damaged or infected. Therefore, these cells release a plethora of chemokines and cytokines that not only induce an acute inflammatory reaction but also have an impact on the alignment of the following immune reaction. In case of asthma, all these functions are impaired by the already existing allergic immune response that per se weakens the barrier integrity and self-cleaning abilities of the airway epithelium making it more vulnerable to penetration of allergens as well as of infection by bacteria and viruses. Recent studies indicate that the history of allergy- and pathogen-derived insults can leave some kind of memory in these cells that can be described as imprinting or trained immunity. Thus, the airway epithelium is in the center of processes that lead to formation, progression and acute exacerbation of asthma.

Keywords: asthma; barrier; imprinting; inflammation; mucus; polarization; trained immunity.

FIGURE 1

Protection of epithelial surfaces by physical barriers. In the healthy state, ciliated cells (CC) form a tight epithelial layer where paracellular passage is prevented by sealing of lateral intercellular spaces with tight junctions (TJ). The apical epithelial cell surface, including the cilia, is covered by a layer of membrane-anchored glycoproteins and glycolipids, the glycocalyx. The dense meshwork of glycostructures restricts access of luminal matter to the apical cell surface; depending on their size, larger pathogens can be cut off from their receptor if it is not present on cilia (inset). Goblet cells (GC) secrete mucus, consisting of highly glycosylated mucins which absorb large quantities of water to form a viscous gel. The mucus – and any matter trapped within – is transported upward in the airway lumen by the coordinated beating of the cilia. BC, basal cells. In the asthmatic state, barrier functions can be compromised by partial disruption of tight junctions and gaps in the PCL/glycocalyx meshwork due to loss of cilia. Mucus clearance is impeded by increased mucus viscosity and swelling of the gel matrix, and by disturbance of ciliar beating due to disorganization and dykinesia of cilia.

FIGURE 2

Release of immunoglobulin A at epithelial surfaces. Dimeric IgA is released submucosally by B cells and binds to the poly Ig receptor (pIgR) which is found in high amounts in the basolateral membrane of the epithelium in the healthy state. The complex of pIgR and dimeric IgA is transported in secretory vesicles to the apical side, where it is released into the lumen as secreted IgA (sIgA) to bind target antigens/allergens/pathogens and entrap them in mucus. In the asthmatic state, the amount of pIgR in the epithelium appears to be reduced, resulting in diminished secretion of sIgA and futile accumulation of IgA in the subepithelial compartment.

FIGURE 3

Inflammatory response of the airway epithelium during stable allergic asthma and exacerbation. During stable allergic asthma airway epithelial cells (AECs) release IL-25, IL-33 and TSLP supporting differentiation of T helper (TH) 2 cells that are activated by dendritic cells (DCs). Th2 cells in turn secrete IL-5 and GM-CSF that together with AEC-derived eotaxins, RANTES and MCPs regulate the production, maturation, recruitment and activation of eosinophils. Local degranulation of eosinophils in the lung eventually leads to damage of the airway epithelium. In parallel, the TH2-type cytokines IL-9 and IL-13 induce goblet cell (GC) metaplasia in airway epithelium. During viral induced asthma exacerbations, several other additional factors lead to an aggravation of this inflammatory response. Viral infection can be detected by the airway epithelium via pattern recognition receptors (PRR). Subsequently, AECs secrete on the one hand TARC, the main chemokine for the recruitment of Th17 cells that amplifies the proinflammatory effects of Th2 cells via release of IL-17, and on the other hand IL-8, which leads to the recruitment of neutrophils. Local degranulation of neutrophils in the lung eventually leads to additional damage of the airway epithelium. Viral infection of AECs also directly leads to damage of the airway epithelium. In summary, these conditions result in a markedly increased damage of the airway epithelium compared to the stable disease, which further impairs barrier integrity and leads to release of matrikines further amplifying the ongoing inflammation.

FIGURE 4

Mechanisms of allergic inflammation in epithelial cells. The role of tissue cells in the early phase of disease is largely unknown, but could provide important information about the pathologic development and could help to identify the causal relationships. However, bronchial epithelial cells are pre-committed to a type-2 (E2) or type-1 (E1) like phenotype. E2 epithelial cell activation by allergens takes place and their pro-inflammatory cytokines and chemokines induce inflammation and contribute to an epithelial type-2 response, so called “E2 response” with epithelial alarmins TSLP, IL-31, CCL-26, IL-25, and IL-33. Local type-2 responses involve multiple cytokines such as IL-4, IL-5, IL-9, IL-13, IL-25, IL-33, and increase of eosinophils. A series of chemokines are produced and migration of inflammatory cells to the allergic tissues takes place. The activation of e.g., smooth muscle cells by ADAM33 lead to remodeling. Bronchial hyperreactivity takes place leading to an enhanced susceptibility to bronchoconstriction. E1 epithelial cells respond to an infection releasing CXCL2, CXCL8, IL12 and CCL20, thus stimulating the local synthesis of IFN-γ, IL-2, IL-12, IL-18, IL-36, and TNF-α that present a wide range of antiviral activities, inducing up-regulation 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, leading to the containment of the infection, rise of body temperature and to the recruitment of further phagocytic cells.