Inhibition of NETosis via PAD4 alleviated inflammation in giant cell myocarditis

Zhan Hu; Xiumeng Hua; Xiuxue Mo; Yuan Chang; Xiao Chen; Zhenyu Xu; Mengtao Tao; Gang Hu; Jiangping Song

doi:10.1016/j.isci.2023.107162

Inhibition of NETosis via PAD4 alleviated inflammation in giant cell myocarditis

iScience. 2023 Jun 16;26(7):107162. doi: 10.1016/j.isci.2023.107162. eCollection 2023 Jul 21.

Authors

Zhan Hu^{1

2}, Xiumeng Hua^{1

2

3

4}, Xiuxue Mo⁵, Yuan Chang^{1

2

3

4}, Xiao Chen^{3

4}, Zhenyu Xu^{3

6}, Mengtao Tao^{3

4}, Gang Hu⁵, Jiangping Song^{1

2

3

4}

Affiliations

¹ Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
² Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
³ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
⁴ The Cardiomyopathy Research Group at Fuwai Hospital, Tianjin 300071, China.
⁵ School of Statistics and Data Science, LPMC and KLMDASR, Nankai University, Tianjin 300071, China.
⁶ Department of Pathology Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

Abstract

Giant cell myocarditis (GCM) is a rare, usually rapidly progressive, and potentially fatal disease. Detailed inflammatory responses remain unknown, in particular the formation of multinucleate giant cells. We performed single-cell RNA sequencing analysis on 15,714 Cd45⁺ cells extracted from the hearts of GCM rats and normal rats. NETosis has been found to contribute to the GCM process. An inhibitor of NETosis, GSK484, alleviated GCM inflammation in vivo. MPO (a marker of neutrophils) and H3cit (a marker of NETosis) were expressed at higher levels in patients with GCM than in patients with DCM and healthy controls. Imaging mass cytometry analysis revealed that immune cell types within multinucleate giant cells included CD4⁺ T cells, CD8⁺ T cells, neutrophils, and macrophages but not B cells. We elucidated the role of NETosis in GCM pathogenesis, which may serve as a potential therapeutic target in the clinic.

Keywords: Cardiovascular medicine; Immunology; Transcriptomics.