The immune checkpoint TIM-3/HMGB-1 axis in myocardial infarction
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.
Authors
- Tamás G. Gergely (ORCID: https://orcid.org/0000-0003-1972-2065)
- Przemysław Leszek (ORCID: https://orcid.org/0000-0003-4529-2687)
- Roy Oelen (ORCID: https://orcid.org/0000-0002-5026-6531)
- Rudolf A. de Boer (ORCID: https://orcid.org/0000-0002-4775-9140)
- Joseph Pierre Aboumsallem (ORCID: https://orcid.org/0000-0001-8186-6620)
- Elles M. Screever (ORCID: https://orcid.org/0000-0002-3093-7836)
- Hilde E. Groot (ORCID: https://orcid.org/0000-0002-8265-3085)
- Irene V. van Blokland (ORCID: https://orcid.org/0000-0002-8545-8015)
- Zoltán V. Varga (ORCID: https://orcid.org/0000-0002-2758-0784)
- Laura I. Yousif
- Monique G.P. van der Wijst (ORCID: https://orcid.org/0000-0003-1520-3970)
- Wouter C. Meijers (ORCID: https://orcid.org/0000-0002-3287-6766)
- Lude Franke (ORCID: https://orcid.org/0000-0002-5159-8802)
- Michael G. Kocsis
- Erik Lipšic (ORCID: https://orcid.org/0000-0002-7407-3064)
- Pim van der Harst
- Aukje G. Sijtema
Institutions
- Semmelweis University (HU)
- University Medical Center Groningen (NL)
- University Medical Center Utrecht (NL)
- Montavid Thermodynamic Research Group (HU)
- Institute of Cardiology (PL)
- Erasmus MC Cancer Institute (NL)
- Cardinal Stefan Wyszynski University in Warsaw (PL)
Publication Details
- Journal
- npj Cardiovascular Health
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1038/s44325-025-00061-x
- Citations
- 3
- Primary Topic
- Galectins and Cancer Biology
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- Bristol-Myers Squibb
- AstraZeneca
- Biogen
- European Commission
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Oncode Institute
- HORIZON EUROPE Framework Programme
- Daiichi Sankyo Europe