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Title: The role of chemerin and chemerin derived peptides in inflammation
Author: Regan-Komito, Daniel
ISNI:       0000 0004 6497 7566
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Inflammation is a normal physiological response to invading pathogens or tissue injury. However, if the inciting stimulus is not efficiently cleared, the inflammatory response is not resolved and becomes chronic. Chronic inflammation plays an important role in the pathology of a variety of diseases including atherosclerosis, rheumatoid arthritis, multiple sclerosis, psoriasis, colitis and cancer. Understanding this disease process and its regulation is of paramount importance for the development of novel therapies for these diseases. Chemerin was originally isolated from inflammatory exudate fluid and found to be a ligand for the orphan G-protein coupled receptor, ChemR23. Secreted in an inactive pro- form, pro-chemerin, the carboxyl terminus can be cleaved by different proteases to generate active chemerin isoforms. Active chemerin is a chemoattractant for immature dendritic cells, natural killer cells and macrophages. The role played by chemerin during chronic inflammation remains controversial. It has been reported to be elevated in patients with a number of inflammatory and metabolic diseases but chemerin and shorter chemerin derived peptides have also been reported to exert anti-inflammatory effects in pre-clinical murine models. In this thesis, I set out to investigate what role chemerin plays during inflammation. I demonstrated that chemerin can exert both pro- and anti-inflammatory effects depending on the time of intervention. During a standard model of acute inflammation (zymosan induced peritonitis), pre-treatment of animals with recombinant murine chemerin increased neutrophil recruitment while administration of chemerin into an already inflamed peritoneum significantly reduced monocyte recruitment. These effects are likely due to further proteolytic processing of active chemerin as demonstrated by the incubation of active chemerin with neutrophil derived proteases, which produced shorter bioactive peptides. Chemerin binds to three receptors, ChemR23, GPR1 and CCRL2. Both ChemR23 and GPR1 have been demonstrated to induce downstream signalling following chemerin binding but CCRL2 does not. CCRL2 is expressed on a range of cell types and its expression is rapidly increased following inflammatory stimuli. However, its role in inflammation remains largely unknown. I have demonstrated that animals lacking the CCRL2 chemerin receptor display exaggerated monocyte and neutrophil recruitment during acute inflammatory responses. This phenotype does not seem to be due to increased levels of total chemerin either locally or systemically, nor does it seem to be due to differences in local inflammatory mediator production. I observed increased neutrophils in the blood of these animals during acute inflammatory responses, indicating CCRL2 may play a role in dampening neutrophil mobilisation from bone marrow rather then exerting effects locally. Taken together the experiments presented in this thesis suggest that targeting chemerin therapeutically may be of benefit in certain contexts but not in others. In addition, the non-signalling chemerin receptor CCRL2 plays a non-redundant role in regulating neutrophil and monocyte recruitment to local sites of inflammation as well as mobilisation of neutrophils into the blood stream.
Supervisor: Greaves, David ; Iqbal, Asif Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available