BS31 The role of fractalkine and CX3CR1-expressing lymphocytes during myocardial ischaemia/reperfusion injury. (May 2019)

• Record Type: Journal Article
• Authors: Draganova, Lilia; Redgrave, Rachael; Tual-Chalot, Simon; Marsh, Sarah; Arthur, Helen; Spyridopoulos, Ioakim
• Is Part Of: Heart. Volume 105(2019)Supplement 6
• Page Start: A160
• Page End: A160
• Publication Date: 2019-05
• Subjects: Myocardial infarction -- Ischaemia/Reperfusion -- CX3CR1+ T cells; Heart -- Diseases -- Treatment -- Periodicals; Cardiology -- Periodicals; 616.12
• DOI: 10.1136/heartjnl-2019-BCS.194
• Languages: English
• ISSNs: 1355-6037

Abstract

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