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<p>Immune checkpoints are understudied in cardiovascular disease. We investigated the TIM-3 pathway in human serum, peripheral blood mononuclear cells (PBMCs) and cardiac tissue following myocardial infarction (MI). First, TIM-3 ligands in serum, galectin-9 and HMGB-1, were associated with cardiac remodelling 4 months post-MI (<i>n</i> = 357). Next, post-hoc single-cell RNA-sequencing of PBMCs from MI patients (<i>n</i> = 38) and controls (<i>n</i> = 38) revealed acute downregulation of TIM-3 in lymphocytes 24 h post-MI, which occurred after 8 weeks in myeloid cells. In the heart, single-nucleus RNA-sequencing and spatial transcriptomics of MI tissue demonstrated cardiomyocyte HMGB-1 upregulation which could communicate with myeloid TIM-3. Pro-inflammatory macrophages specifically showed significant TIM-3 expression and NLRP3 inflammasome activity. On the protein level, HMGB-1 was also upregulated in the infarcted heart and actively translocated throughout the cells. Finally, in vitro macrophage stimulation with HMGB-1 induced pro-inflammatory polarization (e.g. NLRP3 pathway activation), which was prevented by blocking TIM-3. Thus, TIM-3/HMGB-1 interaction presents as a target in cardiac inflammation following MI.</p><p></p>

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The immune checkpoint TIM-3/HMGB-1 axis in myocardial infarction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月27日

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  • Laura I. Yousif,
  • Aukje G. Sijtema,
  • Ymke Appels,
  • Elles M. Screever,
  • Irene V. van Blokland,
  • Roy Oelen,
  • Hilde E. Groot,
  • Tamás G. Gergely,
  • Márton Kocsis,
  • Przemyslaw Leszek,
  • Zoltán V. Varga,
  • Joseph Pierre Aboumsallem,
  • Pim van der Harst,
  • Lude H. Franke,
  • Monique G. P. van der Wijst,
  • Rudolf A. de Boer,
  • Erik Lipšic,
  • Wouter C. Meijers

摘要

Immune checkpoints are understudied in cardiovascular disease. We investigated the TIM-3 pathway in human serum, peripheral blood mononuclear cells (PBMCs) and cardiac tissue following myocardial infarction (MI). First, TIM-3 ligands in serum, galectin-9 and HMGB-1, were associated with cardiac remodelling 4 months post-MI (n = 357). Next, post-hoc single-cell RNA-sequencing of PBMCs from MI patients (n = 38) and controls (n = 38) revealed acute downregulation of TIM-3 in lymphocytes 24 h post-MI, which occurred after 8 weeks in myeloid cells. In the heart, single-nucleus RNA-sequencing and spatial transcriptomics of MI tissue demonstrated cardiomyocyte HMGB-1 upregulation which could communicate with myeloid TIM-3. Pro-inflammatory macrophages specifically showed significant TIM-3 expression and NLRP3 inflammasome activity. On the protein level, HMGB-1 was also upregulated in the infarcted heart and actively translocated throughout the cells. Finally, in vitro macrophage stimulation with HMGB-1 induced pro-inflammatory polarization (e.g. NLRP3 pathway activation), which was prevented by blocking TIM-3. Thus, TIM-3/HMGB-1 interaction presents as a target in cardiac inflammation following MI.