Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis

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...

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Main Authors: Fei Wang, Haiyi Deng, Maolin Zhou, Yilin Yang, Jiankui Zhou, Yansheng Wang, Xiaohong Xie, Xinqing Lin, Ming Liu, Gengyun Sun, Chengzhi Zhou
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
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Summary: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.
ISSN:2041-4889

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