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Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma
Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

Background: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. Objective: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. Methods: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. Results: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13–induced TH2 signature and IL-1 receptor–like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. Conclusion: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.

C-reactive protein, eosinophil, exhaled nitric oxide, IL-1α, IL-1β, IL-33 receptor, inflammasome, neutrophil, Severe asthma, T2
0091-6749
560-570
Rossios, Christos
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Pavlidis, Stelios
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Hoda, Uruj
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Kuo, Chih Hsi
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Wiegman, Coen
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Russell, Kirsty
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Sun, Kai
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Loza, Matthew J.
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Baribaud, Frederic
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Durham, Andrew L.
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Ojo, Oluwaseun
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Lutter, Rene
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Rowe, Anthony
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Bansal, Aruna
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Auffray, Charles
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Sousa, Ana
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Corfield, Julie
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Djukanovic, Ratko
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Guo, Yike
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Sterk, Peter J.
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Chung, Kian Fan
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Adcock, Ian M.
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Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) Consortia Project Team
Rossios, Christos
e9a1316d-e438-4ec1-bbab-90180c578bcc
Pavlidis, Stelios
2b3c21ce-683d-4fde-aae6-e68e05bdb69e
Hoda, Uruj
979a6de0-269b-4d8f-a1e9-58b42c81a774
Kuo, Chih Hsi
bd269315-3c2d-4ee2-9788-2e05cd1d8dc0
Wiegman, Coen
1cbae3f7-5ee7-4b5c-a934-efa11e8a2b30
Russell, Kirsty
d55c9ff5-9f4e-4824-bffd-5aebb470a573
Sun, Kai
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Loza, Matthew J.
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Baribaud, Frederic
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Durham, Andrew L.
6d44bd02-ba3a-49a0-a66d-e398b1816af6
Ojo, Oluwaseun
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Lutter, Rene
8f82687b-826c-4d4a-b2fa-a30cf7d26da2
Rowe, Anthony
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Bansal, Aruna
8782dfea-0663-48b5-a15c-1c01823a131f
Auffray, Charles
16fdf8f6-e7bc-4559-b6b6-d425160867c6
Sousa, Ana
0051d339-a8d8-469b-a0f6-e471372a8478
Corfield, Julie
3709614a-7bb0-4657-8eec-6f40a32fda7e
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Guo, Yike
d6d31305-f913-4954-ba68-5c0ee7fc17be
Sterk, Peter J.
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Chung, Kian Fan
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Adcock, Ian M.
427153bc-3b8b-4066-aa4e-5bc41a6c36dd

Rossios, Christos, Pavlidis, Stelios, Hoda, Uruj, Kuo, Chih Hsi, Wiegman, Coen, Russell, Kirsty, Sun, Kai, Loza, Matthew J., Baribaud, Frederic, Durham, Andrew L., Ojo, Oluwaseun, Lutter, Rene, Rowe, Anthony, Bansal, Aruna, Auffray, Charles, Sousa, Ana, Corfield, Julie, Djukanovic, Ratko, Guo, Yike, Sterk, Peter J., Chung, Kian Fan and Adcock, Ian M. , Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) Consortia Project Team (2018) Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. Journal of Allergy and Clinical Immunology, 141 (2), 560-570. (doi:10.1016/j.jaci.2017.02.045).

Record type: Article

Abstract

Background: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. Objective: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. Methods: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. Results: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13–induced TH2 signature and IL-1 receptor–like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. Conclusion: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.

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More information

Accepted/In Press date: 1 February 2017
e-pub ahead of print date: 17 May 2017
Published date: 1 February 2018
Keywords: C-reactive protein, eosinophil, exhaled nitric oxide, IL-1α, IL-1β, IL-33 receptor, inflammasome, neutrophil, Severe asthma, T2

Identifiers

Local EPrints ID: 419423
URI: http://eprints.soton.ac.uk/id/eprint/419423
ISSN: 0091-6749
PURE UUID: c0729dbd-af86-47fe-af2c-fcf43f87b8e8
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

Catalogue record

Date deposited: 12 Apr 2018 16:30
Last modified: 26 Nov 2021 02:33

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Contributors

Author: Christos Rossios
Author: Stelios Pavlidis
Author: Uruj Hoda
Author: Chih Hsi Kuo
Author: Coen Wiegman
Author: Kirsty Russell
Author: Kai Sun
Author: Matthew J. Loza
Author: Frederic Baribaud
Author: Andrew L. Durham
Author: Oluwaseun Ojo
Author: Rene Lutter
Author: Anthony Rowe
Author: Aruna Bansal
Author: Charles Auffray
Author: Ana Sousa
Author: Julie Corfield
Author: Yike Guo
Author: Peter J. Sterk
Author: Kian Fan Chung
Author: Ian M. Adcock
Corporate Author: Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) Consortia Project Team

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