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BS31 The role of fractalkine and CX3CR1-expressing lymphocytes during myocardial ischaemia/reperfusion injury
  1. Lilia Draganova1,
  2. Rachael Redgrave2,
  3. Simon Tual-Chalot1,
  4. Sarah Marsh1,
  5. Helen Arthur1,
  6. Ioakim Spyridopoulos2
  1. 1Newcastle University
  2. 2Institute of Genetic Medicine, Newcastle University

Abstract

Introduction Primary percutaneous coronary intervention (PPCI) is the standard care for treatment of acute myocardial infarction, reducing both mortality and morbidity. However, ischaemia/reperfusion (I/R) injury remains an important complication, contributing up to 50% of the final infarct size. Evidence from our clinical studies suggests that lymphocytes expressing the fractalkine receptor (CX3CR1) are associated with microvascular obstruction and hence poorer long-term patient outcomes. This project aims to investigate the role of fractalkine in lymphocyte-mediated myocardial I/R injury and evaluate whether this damage can be reduced by inhibiting fractalkine/receptor (CX3CL1/CX3CR1) interaction.

Methods We are using a mouse model of myocardial I/R injury to study lymphocyte infiltration following MI. Multicolour flow cytometry, immunofluorescence staining, qPCR, imaging mass cytometry and magnetic resonance imaging (MRI) are used to evaluate T cell recruitment and cardiac function in a CX3CR1 knockout mouse line.

Results CX3CR1 knockout leads to over 30% reduction in immune cell infiltration at the site of cardiac ischaemic injury 2 hours after reperfusion, both in heterozygous (p ≤ 0.01) and knockout (p ≤ 0.001) mice. By 24 hours I/R, infiltration of CD45+ cells in heterozygous and knockout animals returns to, and surpasses, wild type (WT) levels (p ≤ 0.05). Despite the 20% increase in leukocyte infiltration at 24 hours, we see a 2-fold decrease in T cells at the site of I/R injury in the knockout animals, compared to both WT (p ≤ 0.001) and heterozygous mice (p ≤ 0.0001). T cell infiltration in the knockout is also reduced (although not significantly) when heart infiltrates at 24h reperfusion are investigated by an alternative method: flow cytometry analysis of digested cardiac tissue. Furthermore, our studies show a reduction of 30% in the number of CX3CR1-expressing T cells (p ≤ 0.0001) and 50% in total CX3CR1+ cells (p ≤ 0.01) that infiltrate the left ventricle wall in knockout mice, compared to heterozygous animals. Functional studies using cardiac MRI show no difference between heterozygous and KO mice 6 weeks following I/R injury.

Conclusion These findings suggest that knockout of CX3CR1 leads to delayed recruitment of leukocytes following cardiac I/R. This results in an altered immune cell infiltrate including reduced number of T cells in the injured tissue. In addition, the role for CX3CR1-expressing T cells in myocardial I/R is supported by our data showing that the number of CX3CR1+ CD3+ cells is significantly reduced from heterozygous to knockout animals following injury.

Conflict of interest None

  • Myocardial infarction
  • Ischaemia/Reperfusion
  • CX3CR1+ T cells

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