Location of eosinophils in the airway wall is critical for specific features of airway hyperresponsiveness and T2 inflammation in asthma

Abstract

Eosinophils are implicated as effector cells in asthma but the functional implications of the precise location of eosinophils in the airway wall is poorly understood. We aimed to quantify eosinophils in the different compartments of the airway wall and associate these findings with clinical features of asthma and markers of airway inflammation.In this cross-sectional study, we utilised design-based stereology to accurately partition the numerical density of eosinophils in both the epithelial compartment and the subepithelial space (airway wall area below the basal lamina including the submucosa) in individuals with and without asthma and related these findings to airway hyperresponsiveness (AHR) and features of airway inflammation.Intraepithelial eosinophils were linked to the presence of asthma and endogenous AHR, the type of AHR that is most specific for asthma. In contrast, both intraepithelial and subepithelial eosinophils were associated with type-2 (T2) inflammation, with the strongest association between IL5 expression and intraepithelial eosinophils. Eosinophil infiltration of the airway wall was linked to a specific mast cell phenotype that has been described in asthma. We found that IL-33 and IL-5 additively increased cysteinyl leukotriene (CysLT) production by eosinophils and that the CysLT LTC4 along with IL-33 increased IL13 expression in mast cells and altered their protease profile.We conclude that intraepithelial eosinophils are associated with endogenous AHR and T2 inflammation and may interact with intraepithelial mast cells via CysLTs to regulate airway inflammation.

Identification of Two Eosinophil Subsets in Induced Sputum from Patients with Allergic Asthma According to CD15 and CD66b Expression

“…Studies comparing techniques such as induced sputum and bronchoalveolar lavage for evaluation of airway eosinophils have reported weak correlations [ 23 , 24 ], probably because the techniques evaluate different airway zones (bronchial lumen, subepithelial compartment, and intraepithelial compartment). Since a recent study shows that induced sputum eosinophils correlate with subepithelial eosinophils concentrations [ 25 ], it would be interesting to complement that research with bronchial biopsies to assess whether the two subsets are also present and correlated in the subepithelium and the bronchi. Although it may be thought that the two subsets correspond to different maturation stages, irrespective of location, bronchial eosinophils show a certain degree of activation as a consequence of exposure to inflammatory mediators and expression of membrane proteins as required to migrate [ 26 ].…”

Asthma in elite athletes – do they have Type 2 or non-Type 2 disease? A new insight on the endotypes among elite athletes

“…Presence of intraepithelial mast cells have been described earlier and found as a pathologic characteristic of T2-high asthma (59). Another important finding from Al-Shaikhly et al is the interaction between eosinophils and mast cells within the airway epithelial compartment through LTC 4 -pathways (60). Paucigranulocytic asthma may also be important in athletes, and the absence of neutrophils and eosinophils in sputum in patients with EIB do not exclude the presence of mast cells.…”

Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment

“…This is in contrast to the iEos, which reside primarily in the airway mucosa and evade the sputum [ 2 , 5 ]. An extensive analysis of airway eosinophils supported this point of view while showing that intraepithelial eosinophils are associated with endogenous airway hyperreactivity (AHR) and Type 2 inflammation and may interact with intraepithelial mast cells via cysteinyl leukotrienes (CysLTs) to regulate airway inflammation [ 146 ].…”