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Title: The Role of Fractalkine and CX3CR1-expressing lymphocytes during myocardial ischaemia/reperfusion injury
Authors: Draganova, Lilia Vladimirova
Issue Date: 2020
Publisher: Newcastle University
Abstract: Introduction: Ischaemia/reperfusion (I/R) injury contributes up to 50% of the final infarct size following myocardial infarction (MI). Lymphocytes expressing the fractalkine receptor (CX3CR1) are associated with poor long-term survival. 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: Flow cytometry, microscopy, qPCR, mass cytometry and MRI are used to study lymphocyte infiltration following MI in a surgical mouse model of I/R injury. Results: CX3CR1 knockout leads to over 30% reduction in leukocyte infiltration at the MI site 2h after reperfusion, both in heterozygous (p≤0.01) and knockout (p≤0.001) mice. This returns to WT levels by 24h I/R. Despite the 20% increase in leukocyte infiltration at 24h, CX3CR1 knockout mice show a 2-fold decrease in T cell infiltrate, compared to WT (p≤0.01) and heterozygous animals (p≤0.001). Knockout mice show 30% reduction in the number of CX3CR1-expressing T cells and 50% in total CX3CR1+ cells (p≤0.01) that infiltrate the injured myocardium. MRI shows a trend towards more detrimental cardiac function in CX3CR1 heterozygous and knockout mice. Moreover, RAG2 knockout mice show non-significant 35% increase (p=0.067) in leukocyte infiltrate. Finally, significant T cell maturation and increase in CX3CR1 expression is detected in mouse models of ageing and infection. Conclusions: 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 addition, the role for CX3CR1-expressing T cells in myocardial I/R is supported by results showing that the number of CX3CR1+ CD3+ cells is significantly reduced from heterozygous to knockout animals following injury. However, more clinically representative mouse models may be required in order to elucidate the role of CX3CR1+ T cells in myocardial I/R.
Description: PhD Thesis
Appears in Collections:Translational and Clinical Research Institute

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