Zhang Zhenhao, Xiong Yulong, Liu Shangyu, Shen Lishui, Zheng Lihui, Ding Ligang, Wu Linming, Liu Limin, Zhao Minghao, Li Le, Hu Zhao, Zhang Zhuxin, Zhou Likun, Yao Yan
Department of Cardiology, Fuwai Hospital, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China.
Department of Cardiology, Fuwai Hospital, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China.
Int Immunopharmacol. 2025 Oct 10;163:115313. doi: 10.1016/j.intimp.2025.115313. Epub 2025 Aug 5.
CD4 T cells are crucial to the cardiac autoimmunity of myocarditis, with the underlying pathogenesis remaining unclear. Sinomenine hydrochloride, a natural compound from Sinomenium acutum, is reported to protect against some autoimmune diseases. This study aimed to elucidate the role of CD4 T-helper 1 (Th1) cells in regulating inflammatory cell death and investigate the effect of sinomenine hydrochloride on Th1 cells and myocarditis.
Male Balb/c mice were immunized with myosin heavy chain-α peptides to establish the experimental autoimmune myocarditis (EAM) model. RNA sequencing was used to investigate the functions of T cell subsets in the EAM and explore the effect of sinomenine hydrochloride. Flow cytometry was used to analyze the inhibitory effect of sinomenine hydrochloride on Th1 cells.
We observed a novel function of Th1 cells in promoting macrophage pyroptosis, thereby amplifying the immune response in the EAM. Further investigation revealed that the downstream molecule interferon regulatory factor 1 (IRF1) directly bound to the Casp1 gene and initiated its transcription for pyroptosis induction. To address Th1-induced pyroptosis, we found that sinomenine hydrochloride suppressed Th1 cell activation and differentiation in vitro, as well as Th1-induced pyroptosis, heart injury, and cardiac dysfunction in vivo. Further study indicated that sinomenine hydrochloride targeted at Gatm gene to disturb the arginine metabolism of T cells.
Th1 cell-induced M1 macrophage pyroptosis is an essential pathogenic mechanism of EAM. Sinomenine hydrochloride suppresses Th1 cell arginine metabolism, potentially making it a practical approach to treating myocarditis.
