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Airway epithelium–shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signaling
Matthew C. Altman, … , Michael C. Peters, Teal S. Hallstrand
Matthew C. Altman, … , Michael C. Peters, Teal S. Hallstrand
Published August 22, 2019
Citation Information: J Clin Invest. 2019;129(11):4979-4991. https://doi.org/10.1172/JCI126402.
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Research Article Immunology Pulmonology

Airway epithelium–shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signaling

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Abstract

Asthma is a heterogeneous syndrome that has been subdivided into physiologic phenotypes and molecular endotypes. The most specific phenotypic manifestation of asthma is indirect airway hyperresponsiveness (AHR), and a prominent molecular endotype is the presence of type 2 inflammation. The underlying basis for type 2 inflammation and its relationship to AHR are incompletely understood. We assessed the expression of type 2 cytokines in the airways of subjects with and without asthma who were extensively characterized for AHR. Using quantitative morphometry of the airway wall, we identified a shift in mast cells from the submucosa to the airway epithelium specifically associated with both type 2 inflammation and indirect AHR. Using ex vivo modeling of primary airway epithelial cells in organotypic coculture with mast cells, we show that epithelial-derived IL-33 uniquely induced type 2 cytokines in mast cells, which regulated the expression of epithelial IL33 in a feed-forward loop. This feed-forward loop was accentuated in epithelial cells derived from subjects with asthma. These results demonstrate that type 2 inflammation and indirect AHR in asthma are related to a shift in mast cell infiltration to the airway epithelium, and that mast cells cooperate with epithelial cells through IL-33 signaling to regulate type 2 inflammation.

Authors

Matthew C. Altman, Ying Lai, James D. Nolin, Sydney Long, Chien-Chang Chen, Adrian M. Piliponsky, William A. Altemeier, Megan Larmore, Charles W. Frevert, Michael S. Mulligan, Steven F. Ziegler, Jason S. Debley, Michael C. Peters, Teal S. Hallstrand

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Figure 5

Sputum type 2 gene expression is correlated with a shift in mast cells from the submucosa to the airway epithelium.

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Sputum type 2 gene expression is correlated with a shift in mast cells f...
(A and B) The sputum T2GM is correlated with the number of intraepithelial mast cells relative to the area of the basal lamina (Epi MC/BL area) (A), and not with the number of submucosal mast cells relative to the area of the basal lamina (Sub MC/BL area) (B). (C) The sputum T2GM is correlated with the volume density ratio of mast cells in the epithelium relative to the submucosa. (D) Sputum T2GM is also weakly correlated with sputum eosinophil concentration. All associations are by linear regression; shown are regression lines and 95% confidence bounds.
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