Interleukin-38 ameliorates myocardial Ischemia-Reperfusion injury via inhibition of NLRP3 inflammasome activation in fibroblasts through the IL-1R8/SYK axis

作者：Chengliang Pan, Rui Shen, Yan Ding, Zhiyang Li, Chen Dong, Jiangmei Zhang, Ruirui Zhu, Kunwu Yu, Qiutang Zeng · 发表于：International Immunopharmacology · 年份：2024 · DOI：10.1016/j.intimp.2024.113428 · 被引用次数：8 · 研究领域：Inflammasome and immune disorders、Psoriasis: Treatment and Pathogenesis、Adipokines, Inflammation, and Metabolic Diseases

OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSION: IL-38 acts as a potent negative regulator of inflamm...