Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma
© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ..
INTRODUCTION: The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype.
METHODS: Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma.
RESULTS: Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone (BiP, CANX, CALR), ER-associated protein degradation (EDEM1, DERL1) and ER stress-induced apoptosis (DDIT3, PPP1R15A) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs.
CONCLUSION: Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:77 |
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| Enthalten in: |
Thorax - 77(2022), 5 vom: 25. Mai, Seite 443-451 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pathinayake, Prabuddha S [VerfasserIn] |
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| Links: |
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| Themen: |
Allergic lung disease |
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| Anmerkungen: |
Date Completed 14.04.2022 Date Revised 12.05.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1136/thoraxjnl-2020-215979 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM330522175 |
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| 245 | 1 | 0 | |a Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a INTRODUCTION: The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype | ||
| 520 | |a METHODS: Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma | ||
| 520 | |a RESULTS: Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone (BiP, CANX, CALR), ER-associated protein degradation (EDEM1, DERL1) and ER stress-induced apoptosis (DDIT3, PPP1R15A) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs | ||
| 520 | |a CONCLUSION: Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a allergic lung disease | |
| 650 | 4 | |a asthma | |
| 650 | 4 | |a asthma mechanisms | |
| 700 | 1 | |a Waters, David W |e verfasserin |4 aut | |
| 700 | 1 | |a Nichol, Kristy S |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Alexandra C |e verfasserin |4 aut | |
| 700 | 1 | |a Reid, Andrew T |e verfasserin |4 aut | |
| 700 | 1 | |a Hsu, Alan Chen-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Horvat, Jay C |e verfasserin |4 aut | |
| 700 | 1 | |a Wood, Lisa G |e verfasserin |4 aut | |
| 700 | 1 | |a Baines, Katherine J |e verfasserin |4 aut | |
| 700 | 1 | |a Simpson, Jodie L |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, Peter G |e verfasserin |4 aut | |
| 700 | 1 | |a Hansbro, Philip M |e verfasserin |4 aut | |
| 700 | 1 | |a Wark, Peter A B |e verfasserin |4 aut | |
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