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<p>Acute myocardial infarction (AMI) remains a major global health burden and is characterized by profound cardiac inflammation, apoptotic cell death, and impaired myocardial function. While interleukin-15 (IL-15) has been implicated in immune regulation, its precise role in the pathogenesis of AMI has not been clarified. Therefore, this study sought to delineate the functional role of IL-15 in the progression of AMI, with a particular focus on its influence on macrophage-driven inflammation, efferocytosis, and metabolic reprogramming. IL-15 levels were assessed in AMI patients and murine models. To evaluate the impact of IL-15 on cardiac inflammation, apoptosis, and functional outcomes following AMI, <i>IL-15</i> and IL-15 receptor α (<i>IL-15Rα</i>) knockout (KO) mouse models were employed. Mechanistic studies were conducted to investigate IL-15-mediated effects on macrophage efferocytosis, polarization, and metabolic remodeling, with an emphasis on nuclear factor-κB (NF-κB) signaling and glycolytic flux. Elevated IL-15 levels were detected in both the plasma of AMI patients and the cardiac tissues of murine AMI models, correlating with increased disease severity. The genetic deletion of <i>IL-15</i> or <i>IL-15Rα</i> significantly ameliorated cardiac injury by reducing inflammation and apoptosis while preserving myocardial function. Mechanistic analyses revealed that IL-15 impaired macrophage efferocytosis via Mer tyrosine kinase (MERTK) downregulation and promoted M1 polarization via NF-κB pathway activation. Furthermore, IL-15 reprogrammed macrophage metabolism by enhancing glycolytic activity. Ultimately, IL-15 restoration exacerbated cardiac ischemic injury following AMI, serving as a critical regulator of macrophage-mediated inflammation in AMI. These findings highlight the role of IL-15 as a potential therapeutic and prognostic target for mitigating cardiac inflammation and improving myocardial recovery in AMI.</p>

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IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Lei Guo,
  • Zhehui Yin,
  • Ning Zhang,
  • Han Chen,
  • Zhuo Wang,
  • Yuxue Huang,
  • Jiniu Huang,
  • Yayu You,
  • Chenyun Zhang,
  • Qinyi Bao,
  • Shuxin Lei,
  • Jun Jiang,
  • Xiaojie Xie

摘要

Acute myocardial infarction (AMI) remains a major global health burden and is characterized by profound cardiac inflammation, apoptotic cell death, and impaired myocardial function. While interleukin-15 (IL-15) has been implicated in immune regulation, its precise role in the pathogenesis of AMI has not been clarified. Therefore, this study sought to delineate the functional role of IL-15 in the progression of AMI, with a particular focus on its influence on macrophage-driven inflammation, efferocytosis, and metabolic reprogramming. IL-15 levels were assessed in AMI patients and murine models. To evaluate the impact of IL-15 on cardiac inflammation, apoptosis, and functional outcomes following AMI, IL-15 and IL-15 receptor α (IL-15Rα) knockout (KO) mouse models were employed. Mechanistic studies were conducted to investigate IL-15-mediated effects on macrophage efferocytosis, polarization, and metabolic remodeling, with an emphasis on nuclear factor-κB (NF-κB) signaling and glycolytic flux. Elevated IL-15 levels were detected in both the plasma of AMI patients and the cardiac tissues of murine AMI models, correlating with increased disease severity. The genetic deletion of IL-15 or IL-15Rα significantly ameliorated cardiac injury by reducing inflammation and apoptosis while preserving myocardial function. Mechanistic analyses revealed that IL-15 impaired macrophage efferocytosis via Mer tyrosine kinase (MERTK) downregulation and promoted M1 polarization via NF-κB pathway activation. Furthermore, IL-15 reprogrammed macrophage metabolism by enhancing glycolytic activity. Ultimately, IL-15 restoration exacerbated cardiac ischemic injury following AMI, serving as a critical regulator of macrophage-mediated inflammation in AMI. These findings highlight the role of IL-15 as a potential therapeutic and prognostic target for mitigating cardiac inflammation and improving myocardial recovery in AMI.