Dual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
BACKGROUND: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common β (βc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation.
OBJECTIVE: To determine the pathogenesis of βc receptor-mediated inflammation and remodeling in severe asthma and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease.
METHODS: βc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling.
RESULTS: βc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung.
CONCLUSIONS: βc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:153 |
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| Enthalten in: |
The Journal of allergy and clinical immunology - 153(2024), 3 vom: 29. März, Seite 672-683.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Hao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jaci.2023.10.021 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364235187 |
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| 100 | 1 | |a Wang, Hao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade |
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| 500 | |a Date Completed 11.03.2024 | ||
| 500 | |a Date Revised 11.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common β (βc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation | ||
| 520 | |a OBJECTIVE: To determine the pathogenesis of βc receptor-mediated inflammation and remodeling in severe asthma and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease | ||
| 520 | |a METHODS: βc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling | ||
| 520 | |a RESULTS: βc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung | ||
| 520 | |a CONCLUSIONS: βc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Asthma | |
| 650 | 4 | |a CSL311 | |
| 650 | 4 | |a GM-CSF | |
| 650 | 4 | |a IL-3 | |
| 650 | 4 | |a IL-5 | |
| 650 | 4 | |a airway | |
| 650 | 4 | |a antibody | |
| 650 | 4 | |a biologic | |
| 650 | 4 | |a collagen | |
| 650 | 4 | |a common β cytokine | |
| 650 | 4 | |a eosinophils | |
| 650 | 4 | |a fibrosis | |
| 650 | 4 | |a hyperactivity | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a macrophages | |
| 650 | 4 | |a neutrophils | |
| 650 | 4 | |a remodeling | |
| 650 | 4 | |a trabikibart | |
| 650 | 7 | |a Receptors, Cytokine |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a Allergens |2 NLM | |
| 650 | 7 | |a Steroids |2 NLM | |
| 700 | 1 | |a Yip, Kwok Ho |e verfasserin |4 aut | |
| 700 | 1 | |a Keam, Simon P |e verfasserin |4 aut | |
| 700 | 1 | |a Vlahos, Ross |e verfasserin |4 aut | |
| 700 | 1 | |a Nichol, Kristy |e verfasserin |4 aut | |
| 700 | 1 | |a Wark, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Toubia, John |e verfasserin |4 aut | |
| 700 | 1 | |a Kral, Anita C |e verfasserin |4 aut | |
| 700 | 1 | |a Cildir, Gökhan |e verfasserin |4 aut | |
| 700 | 1 | |a Pant, Harshita |e verfasserin |4 aut | |
| 700 | 1 | |a Hercus, Timothy R |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Nick |e verfasserin |4 aut | |
| 700 | 1 | |a Owczarek, Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Lopez, Angel F |e verfasserin |4 aut | |
| 700 | 1 | |a Bozinovski, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Tumes, Damon J |e verfasserin |4 aut | |
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