REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2
Abstract Objective This study aims to investigate whether REDD1 (Regulated in Development and DNA Damage Responses 1) mediates the nuclear-to-cytoplasmic translocation and release of IL-33 in airway epithelial cells induced by house dust mites (HDM). Methods REDD1 expression levels in bronchial asth...
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| Format: | Article |
| Language: | English |
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BMC
2025-02-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03119-7 |
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| author | Tian Luo Wentao Ji Yuxin Gong Lichang Chen Chao Liu Dandan Zhang Xi Li Yanhua Lv |
| author_facet | Tian Luo Wentao Ji Yuxin Gong Lichang Chen Chao Liu Dandan Zhang Xi Li Yanhua Lv |
| author_sort | Tian Luo |
| collection | DOAJ |
| description | Abstract Objective This study aims to investigate whether REDD1 (Regulated in Development and DNA Damage Responses 1) mediates the nuclear-to-cytoplasmic translocation and release of IL-33 in airway epithelial cells induced by house dust mites (HDM). Methods REDD1 expression levels in bronchial asthma patients were validated using public databases, followed by immunohistochemical analysis of REDD1 protein in airway epithelial cells from these patients. An asthma model was then established using HDM-induced 16HBE cell lines, with REDD1 gene knockout performed. The relationship between varying levels of REDD1 expression, Nrf2, and related inflammatory factors was assessed using Western blot and qPCR. To further investigate the role of the REDD1-Nrf2-IL-33 axis in the development of asthma, we employed Nrf2 activators and inhibitors to reassess the impact of REDD1 on IL-33. Results At both mRNA and protein levels, we found that REDD1 was significantly overexpressed in samples from asthma patients (P < 0.05). In vitro, 24-hour exposure to HDM induced a notable nuclear-to-cytoplasmic translocation of IL-33 and increased its levels in the culture medium of 16HBE cells. In addition, HDM treatment significantly upregulated the expression of both REDD1 and Nrf2. Knockdown of REDD1 markedly suppressed HDM-induced IL-33 release and the expression of TNF-α, IL-6, and IL-1β, while enhancing Nrf2 expression. Moreover, treatment with the Nrf2 agonist curcumin inhibited HDM-induced nuclear-to-cytoplasmic translocation and extracellular secretion of IL-33, whereas the opposite effect was observed when using the Nrf2 antagonist ML385. Conclusion This study reveals the crucial regulatory role of the REDD1-Nrf2-IL-33 axis in the pathological process of bronchial asthma. REDD1 modulates the expression of IL-33 and other inflammatory factors through the Nrf2 signaling pathway, thereby influencing the onset and progression of asthma. Clinical trial number Not applicable. |
| format | Article |
| id | doaj-art-36d5d306ae8a4e1bb00469c4eeeca569 |
| institution | Kabale University |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj-art-36d5d306ae8a4e1bb00469c4eeeca5692025-02-02T12:37:59ZengBMCRespiratory Research1465-993X2025-02-0126111310.1186/s12931-025-03119-7REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2Tian Luo0Wentao Ji1Yuxin Gong2Lichang Chen3Chao Liu4Dandan Zhang5Xi Li6Yanhua Lv7Zhongshan City People’s Hospital, Xinxiang Medical UniversityDepartment of Respiratory and Critical Care Medicine, Zhongshan City People’s HospitalDepartment of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical UniversityDepartment of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical UniversityDepartment of Respiratory and Critical Care Medicine, Zhongshan City People’s HospitalDepartment of Respiratory and Critical Care Medicine, Zhongshan City People’s HospitalDepartment of Respiratory and Critical Care Medicine, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)Department of Respiratory and Critical Care Medicine, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)Abstract Objective This study aims to investigate whether REDD1 (Regulated in Development and DNA Damage Responses 1) mediates the nuclear-to-cytoplasmic translocation and release of IL-33 in airway epithelial cells induced by house dust mites (HDM). Methods REDD1 expression levels in bronchial asthma patients were validated using public databases, followed by immunohistochemical analysis of REDD1 protein in airway epithelial cells from these patients. An asthma model was then established using HDM-induced 16HBE cell lines, with REDD1 gene knockout performed. The relationship between varying levels of REDD1 expression, Nrf2, and related inflammatory factors was assessed using Western blot and qPCR. To further investigate the role of the REDD1-Nrf2-IL-33 axis in the development of asthma, we employed Nrf2 activators and inhibitors to reassess the impact of REDD1 on IL-33. Results At both mRNA and protein levels, we found that REDD1 was significantly overexpressed in samples from asthma patients (P < 0.05). In vitro, 24-hour exposure to HDM induced a notable nuclear-to-cytoplasmic translocation of IL-33 and increased its levels in the culture medium of 16HBE cells. In addition, HDM treatment significantly upregulated the expression of both REDD1 and Nrf2. Knockdown of REDD1 markedly suppressed HDM-induced IL-33 release and the expression of TNF-α, IL-6, and IL-1β, while enhancing Nrf2 expression. Moreover, treatment with the Nrf2 agonist curcumin inhibited HDM-induced nuclear-to-cytoplasmic translocation and extracellular secretion of IL-33, whereas the opposite effect was observed when using the Nrf2 antagonist ML385. Conclusion This study reveals the crucial regulatory role of the REDD1-Nrf2-IL-33 axis in the pathological process of bronchial asthma. REDD1 modulates the expression of IL-33 and other inflammatory factors through the Nrf2 signaling pathway, thereby influencing the onset and progression of asthma. Clinical trial number Not applicable.https://doi.org/10.1186/s12931-025-03119-7REDD1Nrf2IL-33Airway epithelium cellsAsthma |
| spellingShingle | Tian Luo Wentao Ji Yuxin Gong Lichang Chen Chao Liu Dandan Zhang Xi Li Yanhua Lv REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2 Respiratory Research REDD1 Nrf2 IL-33 Airway epithelium cells Asthma |
| title | REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2 |
| title_full | REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2 |
| title_fullStr | REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2 |
| title_full_unstemmed | REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2 |
| title_short | REDD1 mediates HDM-induced nuclear-cytoplasmic translocation and release of IL-33 in airway epithelial cells by downregulating Nrf2 |
| title_sort | redd1 mediates hdm induced nuclear cytoplasmic translocation and release of il 33 in airway epithelial cells by downregulating nrf2 |
| topic | REDD1 Nrf2 IL-33 Airway epithelium cells Asthma |
| url | https://doi.org/10.1186/s12931-025-03119-7 |
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