Department of Cardiology, Worldwide Medical Center, Huashan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China.
Eur J Pharmacol. 2022 Nov 5;934:175293. doi: 10.1016/j.ejphar.2022.175293. Epub 2022 Sep 24.
Myocardial infarction is the highest cause of cardiovascular death. Previous studies found that patients with myocardial infarction have elevated serum IL-37 and IL-37 treatment significantly alleviates adverse remodeling in myocardial infarction mice. However, the underlying mechanism of IL-37 in myocardial infarction is still unknown. Here we explored the underlying mechanism of IL-37 in attenuating myocardial infarction.
The myocardial infarction mice model was constructed by left anterior descending ligation and then submitted to recombinant IL-37 administration. The histology and cardiac function were detected by HE & Masson staining and echocardiography, respectively. The macrophage phenotypes were analyzed by flow cytometry and real-time PCR. The cytokines in serum and cell culture supernatant were determined by ELISA. In addition, THP-1 cells were used in vitro to investigate the underlying mechanisms.
Infarcted mice showed increased inflammatory cell infiltration and impaired cardiac function. IL-37 treatment alleviated pro-inflammatory macrophage infiltration, tissue injury, and collagen deposition in hearts on day 3 and 7 after infarction in mice. In addition, IL-37 application modulated the balance between M1 and M2 macrophages in infarcted hearts. In vitro, THP-1 cell line polarization was also regulated by IL-37, companied by YAP phosphorylation and NLRP3 inactivation. Verteporfin, a YAP inhibitor, could abolish IL-37-induced NLRP3 inhibition and M2 macrophage polarization.
Our results demonstrated that IL-37 achieves a favorable therapeutical function on myocardial infarction by modulating YAP-NLRP3 mediated macrophage programming, providing a promising drug for the treatment of myocardial infarction.
心肌梗死是心血管死亡的最高原因。先前的研究发现，心肌梗死患者的血清 IL-37 水平升高，IL-37 治疗可显著减轻心肌梗死小鼠的不良重构。然而，IL-37 在心肌梗死中的潜在机制尚不清楚。在这里，我们探讨了 IL-37 减轻心肌梗死的潜在机制。
通过左前降支结扎构建心肌梗死小鼠模型，然后给予重组 IL-37 给药。通过 HE 和 Masson 染色和超声心动图分别检测组织学和心脏功能。通过流式细胞术和实时 PCR 分析巨噬细胞表型。通过 ELISA 测定血清和细胞培养上清中的细胞因子。此外，还在体外使用 THP-1 细胞研究潜在机制。
梗死小鼠表现出炎症细胞浸润增加和心脏功能受损。IL-37 治疗可减轻小鼠梗死第 3 天和第 7 天心脏中促炎巨噬细胞浸润、组织损伤和胶原沉积。此外，IL-37 应用可调节梗死心脏中 M1 和 M2 巨噬细胞之间的平衡。体外，IL-37 还调节 THP-1 细胞系的极化，伴有 YAP 磷酸化和 NLRP3 失活。YAP 抑制剂 Verteporfin 可消除 IL-37 诱导的 NLRP3 抑制和 M2 巨噬细胞极化。
我们的结果表明，IL-37 通过调节 YAP-NLRP3 介导的巨噬细胞编程实现对心肌梗死的有利治疗作用，为心肌梗死的治疗提供了一种有前途的药物。
