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IL-13 mediated neutrophilic airway inflammation and hyperresponsiveness is corticosteroid-resistant

IL-13 mediated neutrophilic airway inflammation and hyperresponsiveness is corticosteroid-resistant
IL-13 mediated neutrophilic airway inflammation and hyperresponsiveness is corticosteroid-resistant
Background: effective treatment for severe corticosteroid refractory asthma is a significant unmet clinical need. It affects only a small percent of the asthmatic population but accounts for a disproportionate use of healthcare resources. Recent understanding of asthma heterogeneity has evolved beyond clinical characteristics, allowing definition of distinct disease phenotypes such as those defined by levels of Type 2 inflammation (Type-2 high ‘eosinophilic’ disease and Type-2 low ‘neutrophilic’ disease). A recent study using dupilumab (an antibody that blocks the common IL-4 and IL-13 receptor chain, IL-4Rα) as an add-on therapy in adults with uncontrolled persistent asthma showed efficacy irrespective of baseline eosinophil count. It suggests by blocking the receptor, dupilumab may block IL-4/IL- 13 responses not blocked downstream by corticosteroids. The aim of this work was to use a previously described IL-13 transgenic mouse to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.

Method: lung specific IL-13 expression was induced using Doxycycline (DOX) in Ccsp-rtTA/Otet-Il- 13 double-transgenic (Ccsp/Il-13) mice. Littermate control mice also received DOX. Where indicated, mice received intra-peritoneal injections of 3mg/kg Dexamethasone for 3-7 days and control mice sham-treated with saline. Lung function to methacholine challenge was performed and lungs harvested for mRNA analysis and immunohistochemistry (IHC). BALF was obtained for ELISA and differential cell counts.

Results: as before, Ccsp/Il-13 mice showed significant increase in bronchial hyperresponsiveness (BHR) to methacholine as well as increased bronchial smooth muscle and goblet cell metaplasia. Whilst BALF contained mixed eosinophilic and neutrophilic inflammation, neutrophils predominated. Characteristic Th2-responsive genes as well as genes characteristic of Th17 responses were elevated. Dexamethasone treatment reduced eosinophilia and the associated ‘Th2’ gene signature, but BHR, neutrophil numbers and the ‘Th17’ gene signature remained elevated.

Conclusions: although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory characterized by persistent neutrophilia, Th17 cytokines and maintenance of BHR. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory airway disease.

IL-13, neutrophilic, airway inflammation, airway hyperresponsiveness, corticosteroid-resistant
22-15
Davies, Elizabeth R
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Holgate, Stephen T
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna E
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Davies, Elizabeth R
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Holgate, Stephen T
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna E
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe

Davies, Elizabeth R, Kelly, Joanne, Freda Carmichael, Holgate, Stephen T, Whitsett, Jeffrey A., Davies, Donna E and Haitchi, Hans Michael (2018) IL-13 mediated neutrophilic airway inflammation and hyperresponsiveness is corticosteroid-resistant. 32nd Symposium of the Collegium Internationale Allergologium 2018: Allergy Across the Life Course - From Origins Towards Prevention, , Mallorca, Spain. 30 Sep - 05 Oct 2018. pp. 22-15 .

Record type: Conference or Workshop Item (Other)

Abstract

Background: effective treatment for severe corticosteroid refractory asthma is a significant unmet clinical need. It affects only a small percent of the asthmatic population but accounts for a disproportionate use of healthcare resources. Recent understanding of asthma heterogeneity has evolved beyond clinical characteristics, allowing definition of distinct disease phenotypes such as those defined by levels of Type 2 inflammation (Type-2 high ‘eosinophilic’ disease and Type-2 low ‘neutrophilic’ disease). A recent study using dupilumab (an antibody that blocks the common IL-4 and IL-13 receptor chain, IL-4Rα) as an add-on therapy in adults with uncontrolled persistent asthma showed efficacy irrespective of baseline eosinophil count. It suggests by blocking the receptor, dupilumab may block IL-4/IL- 13 responses not blocked downstream by corticosteroids. The aim of this work was to use a previously described IL-13 transgenic mouse to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.

Method: lung specific IL-13 expression was induced using Doxycycline (DOX) in Ccsp-rtTA/Otet-Il- 13 double-transgenic (Ccsp/Il-13) mice. Littermate control mice also received DOX. Where indicated, mice received intra-peritoneal injections of 3mg/kg Dexamethasone for 3-7 days and control mice sham-treated with saline. Lung function to methacholine challenge was performed and lungs harvested for mRNA analysis and immunohistochemistry (IHC). BALF was obtained for ELISA and differential cell counts.

Results: as before, Ccsp/Il-13 mice showed significant increase in bronchial hyperresponsiveness (BHR) to methacholine as well as increased bronchial smooth muscle and goblet cell metaplasia. Whilst BALF contained mixed eosinophilic and neutrophilic inflammation, neutrophils predominated. Characteristic Th2-responsive genes as well as genes characteristic of Th17 responses were elevated. Dexamethasone treatment reduced eosinophilia and the associated ‘Th2’ gene signature, but BHR, neutrophil numbers and the ‘Th17’ gene signature remained elevated.

Conclusions: although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory characterized by persistent neutrophilia, Th17 cytokines and maintenance of BHR. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory airway disease.

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More information

Published date: 1 October 2018
Venue - Dates: 32nd Symposium of the Collegium Internationale Allergologium 2018: Allergy Across the Life Course - From Origins Towards Prevention, , Mallorca, Spain, 2018-09-30 - 2018-10-05
Keywords: IL-13, neutrophilic, airway inflammation, airway hyperresponsiveness, corticosteroid-resistant

Identifiers

Local EPrints ID: 428126
URI: http://eprints.soton.ac.uk/id/eprint/428126
PURE UUID: 03c465bd-75b8-408d-8cff-a7a78e16de8c
ORCID for Elizabeth R Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for Donna E Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 12 Feb 2019 17:30
Last modified: 10 Nov 2021 03:25

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Contributors

Author: Joanne, Freda Carmichael Kelly
Author: Jeffrey A. Whitsett
Author: Donna E Davies ORCID iD

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