Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma

Association of Differential Mast Cell Activation with Granulocytic Inflammation in Severe Asthma.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1164/rccm.202102-0355OC
Journal or Publication Title: American Journal of Respiratory and Critical Care Medicine
Volume: 205
Number: 4
Page Range: pp. 397-411
Date: 2022
Divisions: UTS Centre for Inflammation
Depositing User: General Admin
Identification Number: 10.1164/rccm.202102-0355OC
ISSN: 1073-449X
Date Deposited: 04 Apr 2022 01:13
Abstract:

Rationale: Mast cells (MCs) play a role in inflammation and both innate and adaptive immunity, but their involvement in severe asthma (SA) remains undefined. Objectives: We investigated the phenotypic characteristics of the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) asthma cohort by applying published MC activation signatures to the sputum cell transcriptome. Methods: Eighty-four participants with SA, 20 with mild/moderate asthma (MMA), and 16 healthy participants without asthma were studied. We calculated enrichment scores (ESs) for nine MC activation signatures by asthma severity, sputum granulocyte status, and three previously defined sputum molecular phenotypes or transcriptome-associated clusters (TACs) 1, 2, and 3 using gene set variation analysis. Measurements and Main Results: MC signatures except unstimulated, repeated FcεR1-stimulated and IFN-γ-stimulated signatures were enriched in SA. A FcεR1-IgE-stimulated and a single-cell signature from asthmatic bronchial biopsies were highly enriched in eosinophilic asthma and in the TAC1 molecular phenotype. Subjects with a high ES for these signatures had elevated sputum amounts of similar genes and pathways. IL-33- and LPS-stimulated MC signatures had greater ES in neutrophilic and mixed granulocytic asthma and in the TAC2 molecular phenotype. These subjects exhibited neutrophil, NF-κB (nuclear factor-κB), and IL-1β/TNF-α (tumor necrosis factor-α) pathway activation. The IFN-γ-stimulated signature had the greatest ES in TAC2 and TAC3 that was associated with responses to viral infection. Similar results were obtained in an independent ADEPT (Airway Disease Endotyping for Personalized Therapeutics) asthma cohort. Conclusions: Gene signatures of MC activation allow the detection of SA phenotypes and indicate that MCs can be induced to take on distinct transcriptional phenotypes associated with specific clinical phenotypes. IL-33-stimulated MC signature was associated with severe neutrophilic asthma, whereas IgE-activated MC was associated with an eosinophilic phenotype.

Creators:
Creators
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Tiotiu, Angelica
UNSPECIFIED
Badi, Yusef
UNSPECIFIED
Kermani, Nazanin Zounemat
UNSPECIFIED
Sanak, Marek
UNSPECIFIED
Kolmert, Johan
UNSPECIFIED
Wheelock, Craig E.
UNSPECIFIED
Hansbro, Philip M.
UNSPECIFIED
Dahlén, Sven-Erik
UNSPECIFIED
Sterk, Peter J.
UNSPECIFIED
Djukanovic, Ratko
UNSPECIFIED
Guo, Yike
UNSPECIFIED
Mumby, Sharon
UNSPECIFIED
Adcock, Ian M.
UNSPECIFIED
Chung, Kian Fan
UNSPECIFIED
Hoda, Uruj
UNSPECIFIED
Rossios, Christos
UNSPECIFIED
Bel, Elisabeth
UNSPECIFIED
Rao, Navin
UNSPECIFIED
Myles, David
UNSPECIFIED
Compton, Chris
UNSPECIFIED
Van Geest, Marleen
UNSPECIFIED
Howarth, Peter
UNSPECIFIED
Roberts, Graham
UNSPECIFIED
Lefaudeux, Diane
UNSPECIFIED
De Meulder, Bertrand
UNSPECIFIED
Bansal, Aruna T.
UNSPECIFIED
Knowles, Richard
UNSPECIFIED
Erzen, Damijn
UNSPECIFIED
Wagers, Scott
UNSPECIFIED
Krug, Norbert
UNSPECIFIED
Higenbottam, Tim
UNSPECIFIED
Matthews, John
UNSPECIFIED
Erpenbeek, Veit
UNSPECIFIED
Carayannopoulos, Leon
UNSPECIFIED
Roberts, Amanda
UNSPECIFIED
Supple, David
UNSPECIFIED
deBoer, Pim
UNSPECIFIED
Caruso, Massimo
UNSPECIFIED
Chanez, Pascal
UNSPECIFIED
Horváth, Ildikó
UNSPECIFIED
Musial, Jacek
UNSPECIFIED
Sandström, Thomas
UNSPECIFIED
Last Modified: 04 Apr 2022 01:13
URI: https://eprints.centenary.org.au/id/eprint/1229

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