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

3 Citations (Scopus)

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

Fingerprint

Matrix Metalloproteinase 9
Adaptive Immunity
Acute Coronary Syndrome
T-Lymphocytes
Stable Angina
Matrix Metalloproteinase Inhibitors
Lymphocyte Activation
T-Cell Antigen Receptor
Flow Cytometry
Theoretical Models
Enzyme-Linked Immunosorbent Assay

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells. / Angelini, Giulia; Flego, Davide; Vinci, Ramona; Pedicino, Daniela; Trotta, Francesco; Ruggio, Aureliano; Piemontese, Giuseppe P.; Galante, Domenico; Ponzo, Myriana; Biasucci, Luigi M.; Liuzzo, Giovanna; Crea, Filippo.

In: European Heart Journal, Vol. 39, No. 13, 01.04.2018, p. 1089-1097.

Research output: Contribution to journalArticle

Angelini, G, Flego, D, Vinci, R, Pedicino, D, Trotta, F, Ruggio, A, Piemontese, GP, Galante, D, Ponzo, M, Biasucci, LM, 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, vol. 39, no. 13, pp. 1089-1097. https://doi.org/10.1093/eurheartj/ehx684
Angelini, Giulia ; Flego, Davide ; Vinci, Ramona ; Pedicino, Daniela ; Trotta, Francesco ; Ruggio, Aureliano ; Piemontese, Giuseppe P. ; Galante, Domenico ; Ponzo, Myriana ; Biasucci, Luigi M. ; Liuzzo, Giovanna ; Crea, Filippo. / Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells. In: European Heart Journal. 2018 ; Vol. 39, No. 13. pp. 1089-1097.
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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.",
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T1 - Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells

AU - Angelini, Giulia

AU - Flego, Davide

AU - Vinci, Ramona

AU - Pedicino, Daniela

AU - Trotta, Francesco

AU - Ruggio, Aureliano

AU - Piemontese, Giuseppe P.

AU - Galante, Domenico

AU - Ponzo, Myriana

AU - Biasucci, Luigi M.

AU - Liuzzo, Giovanna

AU - Crea, Filippo

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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.

KW - Acute coronary syndromes

KW - Adaptive immunity

KW - CD31

KW - MMP-9

KW - Precision medicine

KW - Tailored treatment

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