Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.
Si-Jia SunXiao-Dong JiaoZhi-Gang ChenQi CaoJia-Hui ZhuQi-Rui ShenYi LiuZhen ZhangFang-Fang XuYu ShiJie TongShen-Xi OuyangJiang-Tao FuYi ZhaoJun RenDong-Jie LiFu-Ming ShenPei WangPublished in: Nature communications (2024)
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.
Keyphrases
- high glucose
- diabetic rats
- oxidative stress
- cell death
- mitochondrial dna
- drug induced
- left ventricular
- type diabetes
- heart failure
- endothelial cells
- squamous cell carcinoma
- young adults
- drug delivery
- long non coding rna
- mouse model
- smoking cessation
- single cell
- metabolic syndrome
- living cells
- cell cycle arrest
- atrial fibrillation
- fluorescent probe