Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells

Giulia Angelini, Davide Flego, Ramona Vinci, Daniela Pedicino, Francesco Trotta, Aureliano Ruggio, Giuseppe P. Piemontese, Domenico Galante, Myriana Ponzo, Luigi M. Biasucci, Giovanna Liuzzo, Filippo Crea

Research output: Contribution to journalArticle

Abstract

Aims In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1-5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS. Methods and results To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1-5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (P = 0.002 ACS vs. SA; P = 0.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1-5/6 domain ratio was significantly lower in ACS than in SA (P = 0.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (P < 0.001). CD31 domain 1-5 expression in activated CD4+ T-cells from ACS patients increased after treatment with a specific MMP-9 inhibitor (P = 0.042). Conclusion Our study suggest that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1-5 in CD4+ T-cells of ACS patients. This mechanism might represent an important therapeutic target to modulate T-cell dysregulation in ACS.

Original languageEnglish
Pages (from-to)1089-1097
Number of pages9
JournalEuropean Heart Journal
Volume39
Issue number13
DOIs
Publication statusPublished - Apr 1 2018

Keywords

  • Acute coronary syndromes
  • Adaptive immunity
  • CD31
  • MMP-9
  • Precision medicine
  • Tailored treatment

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Angelini, G., Flego, D., Vinci, R., Pedicino, D., Trotta, F., Ruggio, A., Piemontese, G. P., Galante, D., Ponzo, M., Biasucci, L. M., Liuzzo, G., & Crea, F. (2018). Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells. European Heart Journal, 39(13), 1089-1097. https://doi.org/10.1093/eurheartj/ehx684