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.
View: Text | PDF
Research Article Immunology Pulmonology

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

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

×

Figure 4

A shift in mast cells from the submucosa to the epithelium is associated with indirect AHR.

Options: View larger image (or click on image) Download as PowerPoint
A shift in mast cells from the submucosa to the epithelium is associated...
(A) The number of intraepithelial mast cells relative to the area of the basal lamina (Epi MC/BL area) is increased in asthma compared with healthy controls. (B) It is highest in EIB+ asthma subjects compared with EIB– subjects and healthy controls. (C) Additionally, it is significantly correlated with severity of indirect AHR measured by AUC30. (D–F) In contrast, the number of submucosal mast cells relative to the area of the basal lamina (Sub MC/BL area) is lower in asthma compared with healthy controls (D), is similar in EIB+ and EIB– asthma (E), and is not correlated with indirect AHR (F). (G) The ratio of the number of mast cells per area of the basal lamina in the epithelium relative to the number in the submucosa is increased in asthma. (H) It is highest in the EIB+ asthma subjects relative to the EIB– subjects and healthy controls. (I) Additionally, it is significantly associated with the severity of indirect AHR measured by AUC30. Group comparisons are shown as box plots with median, interquartile range, minimum, and maximum. Significance was assessed by the Mann-Whitney U test (2-group) or the Kruskal-Wallis test with Dunn’s post hoc test for multiple comparisons (3-group). Associations are by linear regression; shown are regression lines and 95% confidence bounds.