Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation

Si-Jia Sun, Xiao-Dong Jiao, Zhi-Gang Chen, Qi Cao, Jia-Hui Zhu, Qi-Rui Shen, Yi Liu, Zhen Zhang, Fang-Fang Xu, Yu Shi, Jie Tong, Shen-Xi Ouyang, Jiang-Tao Fu, Yi Zhao, Jun Ren, Dong-Jie Li (), Fu-Ming Shen () and Pei Wang ()
Additional contact information
Si-Jia Sun: Tongji University
Xiao-Dong Jiao: Naval Medical University/Second Military Medical University
Zhi-Gang Chen: Shanghai
Qi Cao: Naval Medical University/Second Military Medical University
Jia-Hui Zhu: Tongji University
Qi-Rui Shen: Tongji University School of Medicine
Yi Liu: Tongji University
Zhen Zhang: Tongji University
Fang-Fang Xu: Tongji University
Yu Shi: Tongji University
Jie Tong: Tongji University
Shen-Xi Ouyang: Tongji University
Jiang-Tao Fu: Naval Medical University/Second Military Medical University
Yi Zhao: Tongji University
Jun Ren: Fudan University
Dong-Jie Li: Tongji University
Fu-Ming Shen: Tongji University
Pei Wang: Naval Medical University/Second Military Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

Date: 2024
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DOI: 10.1038/s41467-024-50996-5

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