Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Airway Neutrophilia
Heightened unfolded protein responses (UPRs) are associated with the risk for asthma, including severe asthma. Treatment-refractory severe asthma manifests a neutrophilic phenotype with TH17 responses. However, how UPRs participate in the deregulation of TH17 cells leading to neutrophilic asthma remains elusive. This study found that the UPR sensor IRE1 is induced in the murine lung with fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by both human and mouse TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a fungal airway inflammation model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR-mediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
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Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
American journal of respiratory cell and molecular biology - (2024) vom: 09. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wu, Dandan [VerfasserIn] |
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Date Revised 22.04.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Jul 08;:. - PMID 37461622 Citation Status Publisher |
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| doi: |
10.1165/rcmb.2023-0424OC |
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| PPN (Katalog-ID): |
NLM37082783X |
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| 520 | |a Heightened unfolded protein responses (UPRs) are associated with the risk for asthma, including severe asthma. Treatment-refractory severe asthma manifests a neutrophilic phenotype with TH17 responses. However, how UPRs participate in the deregulation of TH17 cells leading to neutrophilic asthma remains elusive. This study found that the UPR sensor IRE1 is induced in the murine lung with fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by both human and mouse TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a fungal airway inflammation model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR-mediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Zhang, Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Zimmerly, Kourtney M |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ruoning |e verfasserin |4 aut | |
| 700 | 1 | |a Livingston, Amanda |e verfasserin |4 aut | |
| 700 | 1 | |a Iwawaki, Takao |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Ashok |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Campen, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Mandell, Michael A |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Meilian |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xuexian O |e verfasserin |4 aut | |
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