Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation
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.
Authors
- Jun Ren (ORCID: https://orcid.org/0000-0002-0275-0783)
- Yu Shi (ORCID: https://orcid.org/0000-0002-2703-1152)
- Yi Zhao (ORCID: https://orcid.org/0000-0002-0958-0350)
- Jiang‐Tao Fu (ORCID: https://orcid.org/0009-0008-6637-7245)
- Qi Cao (ORCID: https://orcid.org/0000-0002-3546-0766)
- Fu‐Ming Shen (ORCID: https://orcid.org/0000-0002-1149-315X)
- Qirui Shen
- Pei Wang (ORCID: https://orcid.org/0000-0002-1650-3353)
- Shen‐Xi Ouyang (ORCID: https://orcid.org/0009-0001-6559-938X)
- Xiao‐Dong Jiao (ORCID: https://orcid.org/0000-0002-9663-8548)
- Jiahui Zhu (ORCID: https://orcid.org/0000-0002-4493-2083)
- Yi Liu (ORCID: https://orcid.org/0000-0002-4998-5547)
- Zhigang Chen (ORCID: https://orcid.org/0000-0001-8903-7042)
- Dongjie Li (ORCID: https://orcid.org/0000-0002-7119-9374)
- Zhen Zhang (ORCID: https://orcid.org/0000-0003-0271-0973)
- Si-Jia Sun
- Jie Tong (ORCID: https://orcid.org/0000-0002-7138-0886)
- Fangfang Xu
Institutions
- Tongji University (CN)
- Sun Yat-sen University (CN)
- Second Military Medical University (CN)
- Fudan University (CN)
- Zhongshan Hospital (CN)
- Shanghai Pulmonary Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Shanghai Tenth People's Hospital (CN)
- Shanghai Skin Disease Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s41467-024-50996-5
- Citations
- 42
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 9.82
Funders
- National Natural Science Foundation of China