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J Clin Invest. 2019 Nov 1;129(11):4979-4991. doi: 10.1172/JCI126402.

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

Author information

1
Division of Allergy and Infectious Diseases and.
2
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
3
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.
4
Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.
5
Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Seattle, Washington, USA.
6
Immunology Program, Benaroya Research Institute, Seattle, Washington, USA.
7
Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
8
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, UCSF, San Francisco, California, USA.

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.

KEYWORDS:

Asthma; Immunology; Mast cells; Pulmonology; Th2 response

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