Lung epithelial cells: Upstream targets in type 2‐high asthma

Abstract

Over the last years, technological advances in the field of asthma have led to the identification of two disease endotypes, namely, type 2‐high and type 2‐low asthma, characterized by different pathophysiologic mechanisms at a cellular and molecular level. Although specific immune cells are important contributors to each of the recognized asthma endotype, the lung epithelium is now regarded as a crucial player able to orchestrate responses to inhaled environmental triggers such as allergens and microbes. The impact of the epithelium goes beyond its physical barrier. It is nowadays considered as a part of the innate immune system that can actively respond to insults. Activated epithelial cells, by producing a specific set of cytokines, trigger innate and adaptive immune cells to cause pathology. Here, we review how the epithelium contributes to the development of Th2 sensitization to allergens and asthma with a “type 2‐high” signature, in both murine models and human studies of this asthma endotype. We also discuss epithelial responses to respiratory viruses, such as rhinovirus, respiratory syncytial virus, and SARS‐CoV‐2, and how these triggers influence not only asthma development but also asthma exacerbation. Finally, we also summarize the results of promising clinical trials using biologicals targeting epithelial‐derived cytokines in asthmatic patients.

Aspergillus and the Lung

“…100 The combination of antibody production and the released cytokines launch mast cell and eosinophil degranulation, thereby releasing additional inflammatory mediators which further aggravate bronchial inflammation and bronchoconstriction. 91,99,101 This type-2 immune response causes the formation of allergic mucin, a significant alteration of the airway mucus, making it elastic and sticky. In all diseases where allergic mucin has been described, including asthma and ABPA, bipyramidal Charcot-Leyden crystals (CLCs) are abundantly present 102,103 (►Figs.…”

Pathobiology of Type 2 Inflammation in Asthma and Nasal Polyposis

“…Other cellular sources of type 2 cytokines include tissue-resident memory T cells (Trm), T follicular helper 2 (Tfh2) and 13 (Tfh13) cells, mast cells, basophils, and eosinophils [11,[33][34][35][36]. Within this pathologic landscape, a key role is played by the dysregulation of airway epithelium, promoted by deleterious agents such as aeroallergens, airborne pollutants, smoking, and viral and bacterial infections, which damage both bronchial epithelial cells and sinonasal epithelial cells, thus stimulating their production of innate cytokines named alarmins [37][38][39]. These include thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and interleukin-33 (IL-33), which act as upstream triggers of innate and adaptive immune mechanisms underlying type 2 inflammation in both upper and lower airways (Figure 1) [37].…”

T-helper cells and their cytokines in pathogenesis and treatment of asthma

“…Asthma is a heterogeneous disease, characterized by major differences in patients’ clinical manifestations, severity, response to treatment, and allergens stimulation ( 1 ). With intensive research on the underlying molecular mechanisms or endotypes of asthma, in recent years, the asthma population has been divided into “Type-2-high” asthma and “Type-2-low” asthma ( 2 ).…”