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Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by il-13

Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by il-13
Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by il-13
Rationale: severe corticosteroid refractory asthma is a significant unmet medical need. It accounts for 10% of the asthma population and 50% of the health economic burden. 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). However, 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 (Wenzel et al, Lancet 2016). The aim of this work was to use IL-13 transgenic mice to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.

Methods: IL-13 expression in the lungs was induced using Doxycycline (DOX) in Ccsp-rtTA/Otet-Il-13 double-transgenic (Ccsp/Il-13) mice. Littermate control single transgenic mice also received DOX. Where indicated, mice received daily intra-peritoneal injections of 3 mg/kg Dexamethasone (Dex) for 3–7 days and control mice received saline. Methacholine challenge and lung function measurements were performed and lungs harvested for mRNA analysis and immunohistochemistry (IHC). BALF was obtained for ELISA and differential cell counts.

Results: compared to controls, Ccsp/Il-13 mice showed significantly increased airway hyperresponsiveness (AHR) to methacholine and IHC revealed increased bronchial smooth muscle and goblet cell metaplasia. The BALF of these mice contained mixed eosinophilic and neutrophilic inflammation, but neutrophils predominated. Characteristic Th2-responsive genes (Il-13, Eotaxin, Muc5ac, Periostin and SerpinB2) as well as genes more characteristic of Th17 responses (Cxcl1/Kc, Cxcl2 and Csf3) were significantly elevated. Treatment with Dex did not abrogate AHR, even though eosinophilia and the ‘Th2’ gene signature were significantly reduced. However, neutrophils and the ‘Th17’ signature remained elevated.

Conclusion: although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory inflammation characterised by persistent neutrophilia, Th17 cytokines and maintenance of AHR. These findings may help explain the beneficial effect of dupilumab in uncontrolled asthma. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory disease.
A53
BMJ
Davies, Elizabeth
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Whitsett, J.A.
3fc6684d-66e9-43b3-98da-2c4c6236fcc3
Holgate, Stephen
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans
68dadb29-305d-4236-884f-e9c93f4d78fe
Davies, Elizabeth
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Whitsett, J.A.
3fc6684d-66e9-43b3-98da-2c4c6236fcc3
Holgate, Stephen
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans
68dadb29-305d-4236-884f-e9c93f4d78fe

Davies, Elizabeth, Kelly, Joanne, Freda Carmichael, Whitsett, J.A., Holgate, Stephen, Davies, Donna and Haitchi, Hans (2017) Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by il-13. In Thorax. vol. 72, BMJ. A53 . (doi:10.1136/thoraxjnl-2017-210983.91).

Record type: Conference or Workshop Item (Paper)

Abstract

Rationale: severe corticosteroid refractory asthma is a significant unmet medical need. It accounts for 10% of the asthma population and 50% of the health economic burden. 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). However, 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 (Wenzel et al, Lancet 2016). The aim of this work was to use IL-13 transgenic mice to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.

Methods: IL-13 expression in the lungs was induced using Doxycycline (DOX) in Ccsp-rtTA/Otet-Il-13 double-transgenic (Ccsp/Il-13) mice. Littermate control single transgenic mice also received DOX. Where indicated, mice received daily intra-peritoneal injections of 3 mg/kg Dexamethasone (Dex) for 3–7 days and control mice received saline. Methacholine challenge and lung function measurements were performed and lungs harvested for mRNA analysis and immunohistochemistry (IHC). BALF was obtained for ELISA and differential cell counts.

Results: compared to controls, Ccsp/Il-13 mice showed significantly increased airway hyperresponsiveness (AHR) to methacholine and IHC revealed increased bronchial smooth muscle and goblet cell metaplasia. The BALF of these mice contained mixed eosinophilic and neutrophilic inflammation, but neutrophils predominated. Characteristic Th2-responsive genes (Il-13, Eotaxin, Muc5ac, Periostin and SerpinB2) as well as genes more characteristic of Th17 responses (Cxcl1/Kc, Cxcl2 and Csf3) were significantly elevated. Treatment with Dex did not abrogate AHR, even though eosinophilia and the ‘Th2’ gene signature were significantly reduced. However, neutrophils and the ‘Th17’ signature remained elevated.

Conclusion: although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory inflammation characterised by persistent neutrophilia, Th17 cytokines and maintenance of AHR. These findings may help explain the beneficial effect of dupilumab in uncontrolled asthma. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory disease.

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More information

e-pub ahead of print date: 15 November 2017
Published date: 6 December 2017

Identifiers

Local EPrints ID: 418373
URI: https://eprints.soton.ac.uk/id/eprint/418373
PURE UUID: 0dfae4a9-7b16-420e-af10-9ff8b48524fa
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Hans Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

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Date deposited: 05 Mar 2018 17:30
Last modified: 24 May 2019 00:40

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