IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk..pdf (831.5 kB)
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IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk.

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journal contribution
posted on 23.07.2015, 10:35 by D. Kaur, E. Gomez, C. Doe, R. Berair, L. Woodman, R. Saunders, F. Hollins, F. R. Rose, Y. Amrani, R. May, J. Kearley, A. Humbles, E. S. Cohen, C. E. Brightling
BACKGROUND: Mast cell localization within the airway smooth muscle (ASM)-bundle plays an important role in the development of airway hyper-responsiveness (AHR). Genomewide association studies implicate the 'alarmin' IL-33 in asthma, but its role in mast cell-ASM interactions is unknown. OBJECTIVES: We examined the expression and functional role of IL-33 in bronchial biopsies of patients with and without asthma, ex vivo ASM, mast cells, cocultured cells and in a mouse model system. METHODS: IL-33 protein expression was assessed in human bronchial tissue from 9 healthy controls, and 18 mild-to-moderate and 12 severe asthmatic patients by immunohistochemistry. IL-33 and ST2 mRNA and protein expression in human-derived ASM, epithelial and mast cells were assessed by qPCR, immunofluorescence and/or flow cytometry and ELISA. Functional assays were used to assess calcium signalling, wound repair, proliferation, apoptosis and contraction. AHR and inflammation were assessed in a mouse model. RESULTS: Bronchial epithelium and ASM expressed IL-33 with the latter in asthma correlating with AHR. ASM and mast cells expressed intracellular IL-33 and ST2. IL-33 stimulated mast cell IL-13 and histamine secretion independent of FcεR1 cross-linking and directly promoted ASM wound repair. Coculture of mast cells with ASM activated by IL-33 increased agonist-induced ASM contraction, and in vivo IL-33 induced AHR in a mouse cytokine installation model; both effects were IL-13 dependent. CONCLUSION: IL-33 directly promotes mast cell activation and ASM wound repair but indirectly promotes ASM contraction via upregulation of mast cell-derived IL-13. This suggests that IL-33 may present an important target to modulate mast cell-ASM crosstalk in asthma.

Funding

The authors thank the following funding bodies: Wellcome Trust Senior Clinical Fellowship (CEB), MedImmune Ltd., Airway Disease Predicting Outcomes through Patient Specific Computational Modelling (AirPROM) project (funded through FP7 EU grant), NC3R and the European Regional Development Fund (ERDF 05567) part-funded the research laboratories. This paper presents independent research funded by the National Institute for Health Research (NIHR).

History

Citation

Allergy, 2015, 70 (5), pp. 556-567

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

Allergy

Publisher

Wiley

issn

0105-4538

eissn

1398-9995

Acceptance date

02/01/2015

Copyright date

2015

Available date

23/07/2015

Publisher version

http://onlinelibrary.wiley.com/doi/10.1111/all.12593/abstract

Notes

Additional Supporting Information may be found in the online version of this article: Data S1. Materials and Methods. Figure S1. Role IL-33 ASM cell proliferation and apoptosis.

Language

en

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