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Title: An investigation of the class C chemokine receptor and ligand and their potential role in the central nervous system
Author: Talbot, Jordan
ISNI:       0000 0004 7966 9531
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Background: XCR1 represents the sole member of the class C chemokine receptor family. In humans, this receptor has two exclusive ligands – XCL1 and XCL2. This chemokine signalling axis demonstrates clear conservation of sequence, structure and function between mice and humans. However only a single ligand, Xcl1, exists in mice. In addition, a lack of clarity surrounds the molecular identity of the Xcr1 protein in mice. Recent evidence from a rat model of peripheral nerve injury has demonstrated the expression of Xcr1 within the CNS and suggests this chemokine signalling axis to contribute to the inflammatory response to central and peripheral nerve injury. Further examination of this chemokine signalling axis was sought to characterise the contribution of XCR1 and XCL1 to CNS function. Aims and Objectives: 1) Determine the molecular identity of mRNA and protein produced by Xcr1. 2) Characterise the expression of Xcr1 and Xcl1 within the mouse CNS. 3) Determine the influence of a central inflammatory response on the gene and protein expression of Xcr1 and Xcl1 within the mouse CNS. 4) Attempt the identification of XCR1 presence within the spinal cord of humans in the context of health and disease. Results: This project provides the first direct functional comparison of the two predicted Xcr1 isoforms and demonstrates higher ß-arrestin recruitment to the Xcr1 protein produced from an open reading frame located entirely within exon 2. The expression of Xcr1 and Xcl1 was observed to be low within the CNS of NTg animals. However, an increase of Xcl1 expression within the spinal cords of mice demonstrating prolific glial activation was observed, whilst the expression of Xcr1 remained unchanged. Attempts to refine the cellular source of Xcl1 expression identified a low expression of Xcl1 within primary microglial preparations from NTg, SOD1-G93A and TDP-Q331K mice. The expression of Xcl1 by these primary cell preparations was not influenced by LPS treatment. Detection of XCR1 within the spinal cord of humans by immunohistochemistry provides the first indication, to our knowledge, of XCR1 expression by glial cells of the white matter. Conclusions: Further credence has been given to the molecular identity of mouse Xcr1 to arise exclusively from exon 2 of Xcr1. The identity of Xcr1 mRNA however remains inconclusive. This has implications for future investigations of the expression of this chemokine receptor, as well as for the development of methodologies to achieve this. Xcr1 and Xcl1 expression is suggested to be low within the CNS of NTg animals. The increased expression of Xcl1 is in accordance with this chemokine to contribute to a central inflammatory response, however this expression is not supported to arise from microglia. The presence of XCR1 within human spinal cord is indicated to localise to glial cells, however further investigation is required to confirm the cellular identity of this expression.
Supervisor: Boissonade, F. M. ; Mead, R. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available