Zhang Hui, Lin Jinyi, Shen Yihui, Pan Jianan, Wang Chunhui, Cheng Leilei
Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, Shanghai, People's Republic of China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, People's Republic of China.
J Inflamm Res. 2022 Mar 5;15:1653-1666. doi: 10.2147/JIR.S348464. eCollection 2022.
Immune checkpoint inhibitors (ICIs)-related myocarditis is now one of the most critical immune-related adverse effects (irAEs) in tumor immunotherapy, which has raised great concern in cardio-oncology. The pathogenesis involved in cardiac injury remains elusive. Crocin, the main component of saffron, has shown distinct functions in cardioprotective and anti-inflammation properties. We therefore aimed to investigate the potential effect of crocin on the protection of ICIs-related myocarditis and its underlying molecular mechanism.
We immunized the BALB/c mice with murine cardiac troponin I (cTnI) peptide and additionally gave anti-mouse programmed death 1 (PD-1) to induce the mouse model of ICIs-related myocarditis. Mice were treated with crocin at different dosages. In vitro, HL-1 cells were pre-incubated with crocin at different concentrations and then stimulated with lipopolysaccharide (LPS). Myocardial contractile functions, myocardial inflammation and fibrosis, and myocardial injury were assessed. The expressions of pyroptosis-related proteins and nuclear factor-κB (NF-κB) pathway were evaluated.
Crocin treatment could partially reverse the ICIs-related myocarditis in terms of improving heart function, ameliorating inflammation and fibrosis in the myocardium, and alleviating myocardial injury. Mechanistically, ICIs administration significantly activated pyrin domain-containing protein 3 (NLRP3) inflammasome in cardiomyocytes. Crocin treatments significantly downregulated the expression of NLRP3, cleaved gasdermin D (GSDMD), cleaved caspase1, interleukin-1β (IL-1β), and IL-18. Besides, crocin inhibited the activation of NF-κB pathway, which performed as reducing the phosphorylation of p-NF-kappa-B inhibitor-α (p-IκBα), degradation of IκBα, phosphorylation of p65 and p65 DNA binding activity both in vivo and in vitro.
By reversing the pyroptosis in cardiomyocytes, crocin treatment in a mouse model exerted great potential to aid in the prevention of ICIs-related myocarditis from a novel target.
免疫检查点抑制剂（ICIs）相关心肌炎是目前肿瘤免疫治疗中最关键的免疫相关不良反应（irAEs）之一，已引起心脏肿瘤学领域的高度关注。心脏损伤的发病机制仍不清楚。藏红花的主要成分西红花苷已显示出明显的心脏保护和抗炎特性。因此，我们旨在研究西红花苷对ICIs相关心肌炎的潜在保护作用及其潜在分子机制。
我们用鼠心肌肌钙蛋白I（cTnI）肽免疫BALB/c小鼠，并额外给予抗小鼠程序性死亡1（PD-1）以诱导ICIs相关心肌炎小鼠模型。小鼠接受不同剂量的西红花苷治疗。在体外，HL-1细胞用不同浓度的西红花苷预孵育，然后用脂多糖（LPS）刺激。评估心肌收缩功能、心肌炎症和纤维化以及心肌损伤。评估焦亡相关蛋白和核因子κB（NF-κB）途径的表达。
西红花苷治疗在改善心脏功能、减轻心肌炎症和纤维化以及减轻心肌损伤方面可部分逆转ICIs相关心肌炎。机制上，给予ICIs可显著激活心肌细胞中含吡咯结构域的蛋白3（NLRP3）炎性小体。西红花苷治疗显著下调NLRP3、裂解的gasdermin D（GSDMD）、裂解的半胱天冬酶1、白细胞介素-1β（IL-1β）和IL-18的表达。此外，西红花苷在体内和体外均抑制NF-κB途径的激活，表现为降低p-NF-κB抑制剂-α（p-IκBα）的磷酸化、IκBα的降解、p65的磷酸化和p65的DNA结合活性。
通过逆转心肌细胞中的焦亡，在小鼠模型中进行西红花苷治疗从一个新的靶点来看，在预防ICIs相关心肌炎方面具有巨大潜力。
