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

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 7

Mast cells regulate the epithelial expression of IL33 in a feed-forward loop.

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Mast cells regulate the epithelial expression of IL33 in a feed-forward ...
In a coculture system with differentiated epithelial cells cocultured with or without mast cells for 48 hours, priming of the mast cells with IL-33 significantly amplified the epithelial expression of IL33. Stimulation of the epithelial surface with HDM further amplified IL33 expression. Similar results were identified for LAD2 mast cells (n = 3 per condition) (A), LUVA mast cells (n = 3 per condition) (B), and primary CBMCs (n = 2 per condition) (C). (D) IL-33 protein was detected in the basolateral media only when IL-33–primed mast cells were added to the coculture system in which HDM was added to the apical surface (n = 4 per condition). IL-33 protein was not detectable when IL-33–primed mast cells that were similarly exposed to HDM were cultured in the absence of the epithelium. Differences between multiple conditions were assessed by 1-way ANOVA with correction for multiple comparisons. Shown are mean values and SEM bars.