CC-chemokine receptors CCR1, CCR2, CCR3, and CCR5 in inflammation

Halawa, Heba Adnan (2023) CC-chemokine receptors CCR1, CCR2, CCR3, and CCR5 in inflammation. PhD thesis, University of Glasgow.

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The CC-chemokine receptors CCR1, CCR2, CCR3, and CCR5 (iCCRs) play a critical role in orchestrating the recruitment of leukocytes to inflamed areas. However, excessive leukocyte accumulation during inflammation can cause tissue damage and various inflammatory disorders, making iCCRs a promising target for therapeutic interventions. Unfortunately, despite extensive research, no iCCR antagonists have been approved for inflammatory and autoimmune diseases due to the apparent complexity of the chemokine system, where individual leukocytes can express multiple chemokine receptors simultaneously and the promiscuity of receptor-ligand interactions. In addition, the need for proper mouse models has hindered our understanding of how iCCRs coordinate the inflammatory response and the development of effective treatments.

The expression of iCCRs in response to specific inflammatory conditions was investigated using BMDMs in vitro. The results indicate that CCR1 and CCR5 are primarily regulated in response to various cytokines and TLR ligands, with CCR1 potentially being further enhanced in response to bacterial infections and CCR5 upregulated in response to viral infections. However, CCR2 and CCR3 did not fluctuate in response to the stimulating agents and remained stable.

Then, using iCCR-reporter mice (iREPs), the temporal changes of iCCR expression in monocytes and differentiated macrophages during sustained inflammation in vivo were assessed. The results show that inflammatory monocytes mainly express reporter CCR2, but a small fraction also co-expresses reporter CCR1 and CCR2, regardless of inflammatory state. We also identified a small subset of inflammatory monocytes that only express reporter CCR1 under sustained inflammation. The transcriptomic analysis of these monocyte subsets shows that they have distinct transcriptional profiles, indicating that multiple iCCR expression does not represent redundant expression.

The findings presented in this thesis have added to our understanding of the role of iCCRs in inflammation by providing information on the regulation of iCCR expression in macrophages and the temporal regulation of iCCRs in monocytes and macrophages during inflammation, and the differential transcriptomes of cells expressing iCCRs. Additional insights into how CCchemokines orchestrate inflammatory responses can be gained from future studies using the iREP mouse model. These insights will not only improve our understanding of basic chemokine biology but also have the potential to guide the development of pharmacological interventions targeting the chemokine system.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Supervisor's Name: Graham, Professor Gerard
Date of Award: 2023
Depositing User: Theses Team
Unique ID: glathesis:2023-83818
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 18 Sep 2023 13:35
Last Modified: 18 Sep 2023 13:57
Thesis DOI: 10.5525/gla.thesis.83818

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