Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113428. doi: 10.1016/j.intimp.2024.113428. Epub 2024 Oct 23.
Although IL-38 is recognized for its regulatory role in a spectrum of chronic inflammatory diseases, investigations into its cardiac physiological and pathophysiological functions are nascent. Our aim was to delineate the biological impact of IL-38 in the context of myocardial ischemia-reperfusion injury (MIRI) and to uncover the mechanisms through which it exerts its effects.
In this study, we used an MIRI mouse model, LPS/ATP stimulation, and a hypoxia/reoxygenation cell model to determine the regulatory influence of IL-38 on MIRI. We observed that the administration of recombinant IL-38 to mice led to a reduction in infarct size, an enhancement in cardiac function, and a suppression of NLRP3 inflammasome activation. In contrast, genetic deletion of IL-38 was associated with an increase in infarct size, worsening of cardiac function, and upregulation of NLRP3 inflammasome activity. The detrimental effects associated with the absence of IL-38 were mitigated by the administration of a specific NLRP3 inhibitor, suggesting that the inhibition of NLRP3 is a critical component of the protective effect mediated by IL-38 in MIRI. In vitro assays revealed that IL-38 inhibited NLRP3 inflammasome activation in cardiac fibroblasts through the engagement of IL-1R8 and the modulation of SYK phosphorylation. Silencing of IL-1R8 negated the suppressive effect of IL-38 on the NLRP3 inflammasome.
IL-38 acts as a potent negative regulator of inflammasome activation after MIRI. It achieves this regulatory effect within cardiac fibroblasts by inhibiting SYK phosphorylation, a process mediated by IL-1R8.
尽管白细胞介素-38（IL-38）因其在一系列慢性炎症性疾病中的调节作用而被广泛认可，但关于其在心肌缺血再灌注损伤（MIRI）中的生理和病理生理学功能的研究仍处于起步阶段。本研究旨在阐明 IL-38 在心肌缺血再灌注损伤中的生物学影响，并揭示其发挥作用的机制。
本研究采用 MIRI 小鼠模型、LPS/ATP 刺激和缺氧/复氧细胞模型，以确定 IL-38 对 MIRI 的调节作用。研究结果表明，给予重组 IL-38 可减少小鼠的梗死面积，改善心功能，并抑制 NLRP3 炎性小体的激活。相反，IL-38 的基因缺失与梗死面积增加、心功能恶化和 NLRP3 炎性小体活性上调相关。给予特异性 NLRP3 抑制剂可减轻缺乏 IL-38 引起的不良影响，表明抑制 NLRP3 是 IL-38 在 MIRI 中发挥保护作用的关键组成部分。体外实验结果显示，IL-38 通过与 IL-1R8 结合并调节 SYK 磷酸化来抑制心肌成纤维细胞中 NLRP3 炎性小体的激活。沉默 IL-1R8 可消除 IL-38 对 NLRP3 炎性小体的抑制作用。
IL-38 是 MIRI 后炎性小体激活的有效负调节剂。它通过抑制 SYK 磷酸化，在心肌成纤维细胞中发挥这种调节作用，该过程由 IL-1R8 介导。
