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Multitissue transcriptomics delineates the diversity of airway T cell functions in asthma

Multitissue transcriptomics delineates the diversity of airway T cell functions in asthma
Multitissue transcriptomics delineates the diversity of airway T cell functions in asthma
Asthma arises from the complex interplay of inflammatory pathways in diverse cell types and tissues. We sought to undertake a comprehensive transcriptomic assessment of the epithelium and airway T cells that remain understudied in asthma, and investigate interactions between multiple cells and tissues. Epithelial brushings and flow-sorted CD3+ T cells from sputum and bronchoalveolar lavage were obtained from healthy subjects (N=19) and asthmatic patients (mild, moderate and severe asthma; N=46). Gene expression was assessed using Affymetrix HT HG-U133+ PM GeneChips and results were validated by real-time quantitative PCR. In the epithelium, IL-13 response genes (POSTN, SERPINB2, CLCA1), mast cell mediators (CPA3, TPSAB1), inducible nitric oxide synthase and cystatins (CST1, CST2, CST4) were upregulated in mild asthma but, except for cystatins, were suppressed by corticosteroids in moderate asthma. In severe asthma – with predominantly neutrophilic phenotype – several distinct processes were upregulated including neutrophilia (TCN1, MMP9), mucins and oxidative stress responses. The majority of the disease signature was evident in sputum T cells in severe asthma, where 267 genes were differentially regulated compared to health, highlighting compartmentalisation of inflammation. This signature included IL-17-inducible chemokines (CXCL1, CXCL2, CXCL3, IL8, CSF3) and chemoattractants for neutrophils (IL8, CCL3, LGALS3), T cells and monocytes. A protein interaction network in severe asthma highlighted signatures of responses to bacterial infections across tissues (CEACAM5, CD14, TLR2) including toll-like receptor signalling. In conclusion, the
82 activation of innate immune pathways in the airways suggests that activated T cells may be driving neutrophilic inflammation and steroid-insensitive IL-17 response in severe asthma.
1044-1549
261-270
Singhania, Akul
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Wallington, Joshua C.
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Smith, Caroline G.
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Horowitz, Daniel
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Staples, Karl J.
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Howarth, Peter H.
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Gadola, Stephan D
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Djukanovic, Ratko
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Woelk, Christopher H.
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Hinks, Timothy S.C.
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Singhania, Akul
322f628d-5374-49ec-b7d7-13bb3885d636
Wallington, Joshua C.
7f2909e0-96f1-4237-b2c2-ea3aa695a9d1
Smith, Caroline G.
c25a9fd1-7974-4c90-86e3-61d4dfc42029
Horowitz, Daniel
0a32e660-bac1-4ad1-a2a1-67bc9743ed46
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Gadola, Stephan D
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Djukanovic, Ratko
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Woelk, Christopher H.
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Hinks, Timothy S.C.
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Singhania, Akul, Wallington, Joshua C., Smith, Caroline G., Horowitz, Daniel, Staples, Karl J., Howarth, Peter H., Gadola, Stephan D, Djukanovic, Ratko, Woelk, Christopher H. and Hinks, Timothy S.C. (2018) Multitissue transcriptomics delineates the diversity of airway T cell functions in asthma. American Journal of Respiratory Cell and Molecular Biology, 58 (2), 261-270. (doi:10.1165/rcmb.2017-0162OC).

Record type: Article

Abstract

Asthma arises from the complex interplay of inflammatory pathways in diverse cell types and tissues. We sought to undertake a comprehensive transcriptomic assessment of the epithelium and airway T cells that remain understudied in asthma, and investigate interactions between multiple cells and tissues. Epithelial brushings and flow-sorted CD3+ T cells from sputum and bronchoalveolar lavage were obtained from healthy subjects (N=19) and asthmatic patients (mild, moderate and severe asthma; N=46). Gene expression was assessed using Affymetrix HT HG-U133+ PM GeneChips and results were validated by real-time quantitative PCR. In the epithelium, IL-13 response genes (POSTN, SERPINB2, CLCA1), mast cell mediators (CPA3, TPSAB1), inducible nitric oxide synthase and cystatins (CST1, CST2, CST4) were upregulated in mild asthma but, except for cystatins, were suppressed by corticosteroids in moderate asthma. In severe asthma – with predominantly neutrophilic phenotype – several distinct processes were upregulated including neutrophilia (TCN1, MMP9), mucins and oxidative stress responses. The majority of the disease signature was evident in sputum T cells in severe asthma, where 267 genes were differentially regulated compared to health, highlighting compartmentalisation of inflammation. This signature included IL-17-inducible chemokines (CXCL1, CXCL2, CXCL3, IL8, CSF3) and chemoattractants for neutrophils (IL8, CCL3, LGALS3), T cells and monocytes. A protein interaction network in severe asthma highlighted signatures of responses to bacterial infections across tissues (CEACAM5, CD14, TLR2) including toll-like receptor signalling. In conclusion, the
82 activation of innate immune pathways in the airways suggests that activated T cells may be driving neutrophilic inflammation and steroid-insensitive IL-17 response in severe asthma.

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Singhania et al 2017 with figures 18-09-2017 - Accepted Manuscript
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Accepted/In Press date: 20 September 2017
e-pub ahead of print date: 21 September 2017
Published date: February 2018

Identifiers

Local EPrints ID: 414299
URI: http://eprints.soton.ac.uk/id/eprint/414299
ISSN: 1044-1549
PURE UUID: 4ab2c06d-b854-44c5-8ecc-74a3998e817a
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

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Date deposited: 26 Sep 2017 16:30
Last modified: 16 Mar 2024 03:52

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Contributors

Author: Akul Singhania
Author: Joshua C. Wallington
Author: Caroline G. Smith
Author: Daniel Horowitz
Author: Karl J. Staples ORCID iD
Author: Stephan D Gadola
Author: Christopher H. Woelk
Author: Timothy S.C. Hinks

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