基于成纤维细胞炎症小体NLRP3探讨IL-38在心肌缺血再灌注损伤中的作用机制

心肌缺血再灌注损伤（MIRI）显著降低急性心肌梗死（AMI）再灌注的疗效，缺乏有效的治疗手段。成纤维细胞炎症小体活化上调促炎因子可加剧MIRI。IL-38能够抑制促炎因子生成并减轻多种慢性炎症疾病。然而，IL-38是否及如何参与MIRI尚不清楚。我们前期研究揭示了AMI再灌注治疗患者外周血IL-38的表达规律以及IL-38能够抑制心脏IL-1β生成和AMI后心肌重塑。预实验发现MIRI可上调心脏IL-38，且重组IL-38显著减少成纤维细胞炎症小体NLRP3活化及心肌细胞凋亡。据此推测：IL-38可抑制成纤维细胞炎症小体NLRP3活化、减少促炎因子释放及心肌细胞凋亡，改善MIRI。为验证此假说，我们拟利用重组IL-38、IL-38-shRNA、多种基因工程小鼠、信号分子抑制剂及IL-1β、IL-18中和抗体，体内及细胞水平验证IL-38在MIRI中的作用机制，为临床防治MIRI提供新靶点。

Myocardial ischemia-reperfusion injury (MIRI) significantly reduces the reperfusion efficiency of acute myocardial infarction (AMI), and currently there is lack of effective means of treatment. As already evidenced, the activation of inflammasome in fibroblasts promotes MIRI via upregulating the production of proinflammatory factors. Interleukin-38 (IL-38) can inhibit proinflammatory factors and alleviate a variety of chronic inflammatory diseases. However, whether and how IL-38 participates in the process of MIRI remains unknown. Our previous research uncovered that the expression of IL-38 in plasma of patients with AMI treated by reperfusion and IL-38 could inhibit IL-1β production in the heart and myocardial remodeling after AMI. Recently, our preliminary studies found that MIRI could upregulate the IL-38 expression in the heart, and the recombinant IL-38 could attenuate the activation of inflammasome NLRP3 in fibroblasts and cardiomyocyte apoptosis. We therefore deduce that IL-38 may inhibit the activation of inflammasome NLRP3 in fibroblasts, and reduce proinflammatory factors and cardiomyocyte apoptosis, ultimately leading to the improvement of MIRI. To test this hypothesis, using the recombinant IL-38, IL-38-shRNA, multiple genetically engineered mice, signaling molecular inhibitors and neutralizing antibodies to IL-1 β and IL-18, we will explore the role and mechanisms of IL-38 in MIRI both in vitro and in vivo. The results are expected to provide a new target for the clinical treatment of MIRI.