Protective Effect of Crocin on Immune Checkpoint Inhibitors-Related Myocarditis Through Inhibiting NLRP3 Mediated Pyroptosis in Cardiomyocytes via NF-[kappa]B Pathway

• Published in: Journal of inflammation research 2022-03, Vol.15, p.1653
• Main Authors: Zhang, Hui, Lin, Jinyi, Shen, Yihui, Pan, Jianan, Wang, Chunhui, Cheng, Leilei
• Format: Article
• Language: English
• Subjects: Analysis; Drug therapy; Heart cells; Immunotherapy; Inflammation; Interleukins; Ipilimumab; Monoclonal antibodies; Myocarditis
• ISSN: 1178-7031; 1178-7031
• DOI: 10.2147/JIR.S348464

Purpose: 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. Methods: 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-[kappa]B (NF-[kappa]B) pathway were evaluated. Results: 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-1[beta] (IL-1[beta]), and IL-18. Besides, crocin inhibited the activation of NF-[kappa]B pathway, which performed as reducing the phosphorylation of p-NF-kappa-B inhibitor-[alpha] (p-I[kappa]B[alpha]), degradation of I[kappa]B[alpha], phosphorylation of p65 and p65 DNA binding activity both in vivo and in vitro. Conclusion: 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. Keywords: cardio-oncology, immune checkpoint inhibitors, autoimmune myocarditis, programmed death 1, immune-related adverse effects