This investigation elucidates the spatiotemporal dynamics of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation following myocardial infarction (MI), a process that has not been fully characterized. We revealed early activation of the NLRP3 inflammasome in mice with MI and characterized its dynamic temporal expression. Notably, the knockout and inhibition of Nlrp3 expression were found to significantly mitigate infarct size and enhance cardiac function. Furthermore, our analysis of the spatial characteristics of inflammasome activation revealed predominant activation in macrophages and subsequent activation in fibroblasts on the third day post-MI. To elucidate the nexus between macrophage-associated NLRP3 inflammasome activation and myocardial fibrosis, we employed targeted metabolomics analyses of inflammatory oxylipins, small interfering RNA (siRNA) interference experiments, and various molecular assays. These findings revealed that macrophage-associated inflammasome activation facilitates the conversion of fibroblasts into myofibroblasts via the 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE)-mediated small mother against decapentaplegic (Smad) pathway. Additionally, both mass spectrometry imaging (MSI) and targeted metabolomics analyses confirmed the significant increase in 15-HETE levels in mice with MI and in patients with MI and acute coronary syndrome (ACS). Our comprehensive dataset suggests that NLRP3 inflammasome activation in MI is characterized by distinct temporal and spatial patterns. These insights mark a significant advancement toward precise MI prevention and treatment strategies, particularly early myocardial fibrosis intervention.

中文翻译：

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在急性心肌梗死中，巨噬细胞相关炎性小体的激活通过 15-HETE 介导的通路加剧心肌纤维化


这项研究阐明了心肌梗死 （MI） 后 NOD 样受体家族包含 3 （NLRP3） 炎性小体激活的时空动力学，这一过程尚未完全表征。我们揭示了 MI 小鼠中 NLRP3 炎性小体的早期激活，并表征了其动态时间表达。值得注意的是，发现敲除和抑制 Nlrp3 表达可显着减轻梗死面积并增强心脏功能。此外，我们对炎性小体激活空间特征的分析显示，在 MI 后第 3 天，巨噬细胞中占主导地位，随后在成纤维细胞中激活。为了阐明巨噬细胞相关 NLRP3 炎性小体激活与心肌纤维化之间的联系，我们采用了炎性氧化磷脂的靶向代谢组学分析、小干扰 RNA （siRNA） 干扰实验和各种分子测定。这些发现揭示了巨噬细胞相关的炎性小体激活通过 15-羟基-5,8,11,13-二十碳四烯酸 （15-HETE） 介导的小母细胞对抗脱瘫 （Smad） 途径促进成纤维细胞转化为肌成纤维细胞。此外，质谱成像 （MSI） 和靶向代谢组学分析证实，MI 小鼠以及 MI 和急性冠脉综合征 （ACS） 患者的 15-HETE 水平显着增加。我们的综合数据集表明，MI 中的 NLRP3 炎性小体激活具有独特的时间和空间模式。这些见解标志着精确的 MI 预防和治疗策略的重大进展，尤其是早期心肌纤维化干预。