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Title: Critical assessment of the role of cannabinoid receptor 2 in inflammation
Author: Kapellos, Theodoros
ISNI:       0000 0004 6497 4242
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Cannabinoid receptor 2 (CB2R) is a G protein-coupled receptor (GPCR) expressed in the periphery by immune cells, such as B cells, natural killer (NK) cells, neutrophils, macrophages and T cells. It belongs to the endocannabinoid system which also comprises CB1R, endogenous lipophilic agonists called endocannabinoids and the enzymes responsible for their synthesis and degradation. During inflammatory diseases the endocannabinoid system is dysregulated and increased expression levels of endocannabinoids and cannabinoid receptors are observed. Therefore there is a continuing interest to target the endocannabinoid system to restore homeostasis in patients who suffer from a number of inflammatory diseases, such as multiple sclerosis, atherosclerosis, neuropathic pain and others. However, to date there has been no good anti-inflammatory drug in the market or clinical trials that acts via CB2R. The main aim of this DPhil thesis was to critically assess the role of this receptor in health and inflammation with a particular focus on innate immune cell recruitment. Here I describe my findings regarding the immunophenotype of a CB2R knockout (KO) mouse strain at steady state and under acute systemic inflammation. I showed that CB2R KO mice display a trend in neutrophil accumulation and in monocyte egress in the bone marrow, as well as higher myeloperoxidase activity in the liver. These findings support the view that this cannabinoid receptor plays a pivotal role in innate immune cell trafficking during homeostasis. Furthermore, I discovered that CB2R KO animals display exacerbated immune cell recruitment to peripheral tissues in a model of low dose endotoxemia. In particular, I found more neutrophils in the lungs and spleens of CB2R KO mice at the model's peak time point. These observations are consistent with a model in which CB2R plays a non-redundant role in the inhibition of neutrophil migration to injured tissues after an inflammatory insult. My in vitro experiments showed that CB2R-selective agonists had no anti-inflammatory effects during macrophage activation. Looking for a mechanistic explanation for this result, I found that the expression levels of the receptor are severely downregulated upon challenge with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) which suggests that it is possible that CB2R is differentially regulated in immune cells during inflammation. Collectively, the data presented in this thesis support the view that CB2R plays an important role in health and disease in pre-clinical models, but further studies are required to make more soluble CB2R-selective agonists and to understand which immune cells we should aim to target therapeutically.
Supervisor: Greaves, David Sponsor: Edward P. Abraham Trust ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available