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

• Published in: The Journal of clinical investigation Vol. 129; no. 11; pp. 4979 - 4991
• Main Authors: Altman, Matthew C., Lai, Ying, Nolin, James D., Long, Sydney, Chen, Chien-Chang, Piliponsky, Adrian M., Altemeier, William A., Larmore, Megan, Frevert, Charles W., Mulligan, Michael S., Ziegler, Steven F., Debley, Jason S., Peters, Michael C., Hallstrand, Teal S.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.11.2019
• Subjects: Asthma; Asthma - immunology; Asthma - pathology; Biomedical research; Cytokines; Epithelial cells; Epithelium; Female; Genomes; Genotype & phenotype; Histamine; Humans; Inflammation; Inflammation - immunology; Inflammation - pathology; Interleukin-33 - immunology; Male; Mast cells; Mast Cells - immunology; Mast Cells - pathology; Morphometry; Phenotypes; Respiratory Mucosa - immunology; Respiratory Mucosa - pathology; Respiratory tract; Signal Transduction - immunology; Studies; Pulmonology; Mast cells; Immunology; Th2 response; Asthma
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI126402

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.