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 8

Feed-forward amplification of epithelial IL33 gene expression is mediated by IL-33 and is not a consequence of IL-13 signaling.

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Feed-forward amplification of epithelial IL33 gene expression is mediate...
(A) A blocking antibody against IL-33 during the 48 hours of coculture reduced the amplification of epithelial IL33 expression during coculture with IL-33–primed LAD2 mast cells, particularly when the apical surface of the epithelium was treated with HDM. (B) Direct treatment of differentiated primary epithelial cells alone (without mast cells) with IL-33 significantly increased the expression of IL33, while treatment with IL-13 did not induce the expression of epithelial IL33. HDM also induced expression of epithelial IL33 (P = 0.02), which was further augmented by treatment with IL-33 in the basolateral compartment and was diminished by the addition of IL-13 in the basolateral fluid. (C) Priming mast cells with IL-33 before coculture increased epithelial IL33 expression in comparison with priming with IL-13 (n = 4 per condition for all conditions, except one condition in which poor quantitative PCR amplification of the housekeeping gene occurred). Differences between multiple conditions were assessed by 1-way ANOVA with correction for multiple comparisons. Shown are mean values and SEM bars.