MCP-1介导的巨噬细胞招募下调在伊布替尼心脏毒性中的作用机制研究

伊布替尼是多种血液系统肿瘤的一线治疗药物，但其诱导心脏毒性是导致患者被迫停药的主要原因，制约药物临床使用，阐明伊布替尼心脏毒性的分子机制对药物临床应用与管理至关重要。巨噬细胞是心脏组织细胞的重要组成部分，在心脏的正常功能维持中起着重要作用。我们前期通过小鼠模型发现：伊布替尼作用后心脏功能减弱，心肌组织中巨噬细胞数量减少，心肌细胞中单核细胞趋化因子（MCP-1）表达下调。由此我们提出科学假说：MCP-1介导的巨噬细胞招募减少，是伊布替尼心脏毒性产生的分子机制。为验证此假说，将借助RNA-seq等技术，阐明MCP-1在伊布替尼减少心脏巨噬细胞中的关键作用；明确转录因子STAT3介导心肌组织中MCP-1的表达，且STAT3活化突变缓解伊布替尼的心脏毒性；最后研究伊布替尼抑制BTK受体下调STAT3信号的机制。本研究为伊布替尼的心脏毒性发生提供分子基础和科学理论，为干预其毒性的发生提供新思路。

Ibrutinib is a widely used Bruton’s tyrosine kinase (BTK) inhibitor that has recently revolutionized the treatment of certain hematological malignancies. However, as experience in using ibrutinib increased, cardiac toxicity emerged as an unexpected side effect, which forced the interruption of ibrutinib treatment. Determination of the cause of cardiotoxicity is pivotal for the clinical application of ibrutinib. Macrophages have been shown to be a vital component in heart and involved in multiple processes. We found that the number of macrophages in the impaired myocardium tissue was decreased in the mouse animal models. The expression of monocyte chemokine (MCP-1) in myocardial cells was down-regulated, which blocked the recruitment of peripheral macrophages. Therefore, we hypothesized that: MCP-1 contributes to ibrutinib-induced cardiotoxicity via down-regulating the recruitment of macrophages. On this basis, further RNA-seq analysis of myocardial tissue revealed that ibrutinib could negatively regulate the activation of STAT3 and subsequently inhibit the expression of MCP-1. Mutations of STAT3 could alleviate the cardiotoxicity of ibrutinib. Hence, our research can not only reveal the molecular basis and scientific theory for the occurrence of ibrutinib cardiotoxicity, and shield light on the intervention of its toxicity.