Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis
Abstract Immune checkpoint inhibitors (ICIs) have significant therapeutic effects but can also cause fatal lung injury. However, the lack of mouse animal models of ICI-related lung injury (ICI-LI) has limited the in-depth exploration of its pathogenesis. In clinical practice, underlying lung disease...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07319-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544234424860672 |
|---|---|
| author | Fei Wang Haiyi Deng Maolin Zhou Yilin Yang Jiankui Zhou Yansheng Wang Xiaohong Xie Xinqing Lin Ming Liu Gengyun Sun Chengzhi Zhou |
| author_facet | Fei Wang Haiyi Deng Maolin Zhou Yilin Yang Jiankui Zhou Yansheng Wang Xiaohong Xie Xinqing Lin Ming Liu Gengyun Sun Chengzhi Zhou |
| author_sort | Fei Wang |
| collection | DOAJ |
| description | Abstract Immune checkpoint inhibitors (ICIs) have significant therapeutic effects but can also cause fatal lung injury. However, the lack of mouse animal models of ICI-related lung injury (ICI-LI) has limited the in-depth exploration of its pathogenesis. In clinical practice, underlying lung diseases increase the risk of lung injury. Thus, we used a mouse model of lung injury induced by bleomycin (BLM) and then administered anti-programmed cell death 1 (aPD-1) antibodies to induce ICI-LI. Compared with the BLM group, the aPD-1 + BLM group presented more significant weight loss, greater levels of lung inflammation and fibrosis, and decreased lung function. In this ICI-LI model, high levels of caspase-3/gasdermin E (GSDME) were detected in the lung tissue of mice, and the JNK inhibitor SP600125 mitigated lung damage by inhibiting GSDME-mediated pyroptosis. Consistent with the findings in the animal model, immunofluorescence and RNA sequencing of lung tissue from ICI-LI patients revealed upregulation of the expression of genes related to the GSDME-related pyroptosis pathway. Our results suggest that GSDME-mediated pyroptosis may be associated with the pathogenesis of ICI-LI, indicating that targeting GSDME could be a potential therapeutic strategy for treating ICI-LI. |
| format | Article |
| id | doaj-art-56f98409dbc141a9a8ecfd132698c377 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-56f98409dbc141a9a8ecfd132698c3772025-01-12T12:41:49ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111210.1038/s41419-024-07319-9Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosisFei Wang0Haiyi Deng1Maolin Zhou2Yilin Yang3Jiankui Zhou4Yansheng Wang5Xiaohong Xie6Xinqing Lin7Ming Liu8Gengyun Sun9Chengzhi Zhou10Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical UniversityState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouPrecise Genome Engineering Center, School of Life Sciences, Guangzhou UniversityState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouDepartment of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical UniversityState Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, GuangzhouAbstract Immune checkpoint inhibitors (ICIs) have significant therapeutic effects but can also cause fatal lung injury. However, the lack of mouse animal models of ICI-related lung injury (ICI-LI) has limited the in-depth exploration of its pathogenesis. In clinical practice, underlying lung diseases increase the risk of lung injury. Thus, we used a mouse model of lung injury induced by bleomycin (BLM) and then administered anti-programmed cell death 1 (aPD-1) antibodies to induce ICI-LI. Compared with the BLM group, the aPD-1 + BLM group presented more significant weight loss, greater levels of lung inflammation and fibrosis, and decreased lung function. In this ICI-LI model, high levels of caspase-3/gasdermin E (GSDME) were detected in the lung tissue of mice, and the JNK inhibitor SP600125 mitigated lung damage by inhibiting GSDME-mediated pyroptosis. Consistent with the findings in the animal model, immunofluorescence and RNA sequencing of lung tissue from ICI-LI patients revealed upregulation of the expression of genes related to the GSDME-related pyroptosis pathway. Our results suggest that GSDME-mediated pyroptosis may be associated with the pathogenesis of ICI-LI, indicating that targeting GSDME could be a potential therapeutic strategy for treating ICI-LI.https://doi.org/10.1038/s41419-024-07319-9 |
| spellingShingle | Fei Wang Haiyi Deng Maolin Zhou Yilin Yang Jiankui Zhou Yansheng Wang Xiaohong Xie Xinqing Lin Ming Liu Gengyun Sun Chengzhi Zhou Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis Cell Death and Disease |
| title | Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis |
| title_full | Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis |
| title_fullStr | Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis |
| title_full_unstemmed | Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis |
| title_short | Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis |
| title_sort | anti pd 1 exacerbates bleomycin induced lung injury in mice via caspase 3 gsdme mediated pyroptosis |
| url | https://doi.org/10.1038/s41419-024-07319-9 |
| work_keys_str_mv | AT feiwang antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT haiyideng antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT maolinzhou antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT yilinyang antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT jiankuizhou antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT yanshengwang antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT xiaohongxie antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT xinqinglin antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT mingliu antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT gengyunsun antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis AT chengzhizhou antipd1exacerbatesbleomycininducedlunginjuryinmiceviacaspase3gsdmemediatedpyroptosis |