TLR4/Myd88/NFκB在免疫检查点抑制剂相关性心肌炎中的作用及机制的研究

The Role and Mechanism of TLR4/Myd88/NFκB in Immune Checkpoint Inhibitor-associated Myocarditis

目的 本研究旨在小鼠模型中探索TLR-4/Myd88/NF-κB与免疫检查点抑制剂相关性心肌炎的关系,为预防或治疗心肌炎提供新的思路。方法 A/J小鼠分成两组,实验组腹腔注射替雷利珠单抗(10 mg·kg^(-1)),对照组腹腔注射100μL PBS缓冲液,每周2次,连续3周。通过超声心动图分析用药前后的左室射血分数、径向和纵向应变。检测用药后小鼠心肌组织中TLR4、MyD88、NF-κB和多种细胞因子的表达。结果 与对照组相比,实验组小鼠的左室射血分数和左心室短轴缩短分数显著减少,同时TLR4、MyD88、p65/NF-κB和IL-1α,IL-1β,IL-2,IL-6,IL-10,IFN-γ等细胞因子在心肌表达显著增加。结论 PD-1抑制剂可能是通过激活TLR4/MyD88/NF-κB通路,诱发心肌炎。

OBJECTIVE To explore the relationship between TLR-4/Myd88/NF-κB and immune checkpoint inhibitor-associated myocarditis in mouse models, and to provide new ideas for the prevention or treatment of myocarditis.METHODS A/J mice were divided into two groups, the experimental group was injected intraperitoneally with Tislelizumab(10 mg·kg^(-1)),and the control group was injected with 100 μL PBS buffer twice a week for three consecutive weeks.Left ventricular ejection fraction, radial, and longitudinal strain before and after administration were analyzed by echocardiography.The expression of TLR4,MyD88,NF-κB,and cytokines in mouse myocardial tissues after administration was detected.RESULTS Compared with the control group, the left ventricular ejection fraction and left ventricular short axis shortening fraction of the experimental group were significantly reduced, while TLR4,MyD88,p65/NF-κB and various cytokines such as IL-1α,IL-1β,IL-2,IL-6,IL-10,IFN-γ were significantly increased in myocardial tissue.CONCLUSION PD-1 inhibitors may induce myocarditis by activating the TLR4/MyD88/NF-κB pathway.