Abstract
Background 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.
Methods 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.
Results Intraepithelial eosinophils were linked to the presence of asthma and endogenous AHR, the type 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 interleukin (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.
Conclusions 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.
Abstract
Intraepithelial eosinophils are a specific feature of asthma, associated with endogenous airway hyperresponsiveness and type 2 inflammation, and may interact with intraepithelial mast cells via cysteinyl leukotrienes to regulate airway inflammation https://bit.ly/3e1QFo1
Footnotes
Author contributions: T.S. Hallstrand and C.W. Frevert conceived of and designed the studies. Y. Lai, J.S. Debley, M. Larmore, M.C. Peters and T.S. Hallstrand performed experiments. T. Al-Shaikhly, A. Parker, J.S. Debley, A.M. Piliponsky, W.A. Altemeier, C.W. Frevert, M.C. Peters and T.S. Hallstrand analysed and interpreted the results of the experiments. T. Al-Shaikhly, R.C. Murphy and T.S. Hallstrand wrote the manuscript. R.C. Murphy, A. Parker, Y. Lai, M.C. Altman, M. Larmore, W.A. Altemeier, C.W. Frevert, J.S. Debley, A.M. Piliponsky, S.F. Ziegler, M.C. Peters and T.S. Hallstrand edited and revised the manuscript, and all authors approved the final version of the manuscript.
Conflict of interest: T. Al-Shaikhly has a patent MicroRNAs as Predictors of Response to Anti-IgE Therapies in Chronic Spontaneous Urticaria pending. M.C. Altman reports personal fees from Sanofi-Regeneron outside the submitted work. W.A. Altemeier reports grants from the National Institute of Health during the conduct of the study. J.S. Debley reports grants from the National Institute of Health during the conduct of the study. A.M. Piliponsky reports grants from the National Institute of Health outside the submitted work. M.C. Peters reports grants from National Institute of Health-NHLBI, Boehringer Ingelheim, AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron and Teva, outside the submitted work. T.S. Hallstrand reports grants from the National Institute of Health during the conduct of the study. The remaining authors report no competing financial interests.
Support statement: The work was supported by the National Institutes of Health (grant numbers: U19AI125378 and K24AI130263). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received July 2, 2021.
- Accepted December 6, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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