Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713294
Title: Regulation of macrophage polarisation by TRIB1 and its consequences in metabolic homeostasis and atherosclerosis
Author: Johnston, Jessica Michelle
ISNI:       0000 0004 6350 4230
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Abstract:
Chronic inflammatory diseases including obesity, diabetes and cardiovascular disease cause significant morbidity and mortality worldwide. It is well established that both circulating lipid levels and macrophages have significant roles in the pathogenesis of these diseases. Single nucleotide polymorphisms (SNPs) close to the Tribbles-1 (TRIB1) gene have been identified in genome wide association studies (GWAS) to be associated with hyperlipidaemia and the incidence of myocardial infarction (MI). Studies using Trib1 full body- and liver specific knockout mice have shown hepatic expression of Trib1 is a regulator of plasma lipid levels, one of the leading risk factors of developing heart disease. Additionally, Trib1 has been shown to be a regulator of 'M2' (alternatively activated) macrophage polarisation. However, the interplay between Trib1, hepatocytes and macrophages is currently unexplored. Similarly, there has been no direct study to evaluate the role of Trib1 in atherogenesis. The aims of this study were to (1) investigate whether myeloid specific alterations of Trib1 expression regulate macrophage polarisation and its consequences on plasma lipid homeostasis; (2) investigate the role of myeloid Trib1 in experimental atherosclerosis and (3) develop immunohistochemistry staining methods to expand the analysis of macrophage phenotype in atherosclerotic plaques. To investigate these aims, myeloid specific Trib1 knockout (Trib1 fl/fl x LyzMCre) and over-expressor (ROSA26.Trib1Tg x LyzMCre) mice were developed and their phenotypes were assessed. Furthermore, the molecular mechanisms by which Trib1 affects macrophage polarisation were investigated. The role of myeloid Trib1 in experimental atherosclerosis was determined by bone marrow transplantation into atherogenic ApoE-/- mice (Trib1 ApoE-/-) and full histological analysis was performed. Moreover, a staining and image analysis method was established to investigate the phenotype of plaque macrophages in situ. Phenotypic analyses of the Trib1 mouse models showed myeloid loss of Trib1 promotes elevated plasma lipids and pro-inflammatory polarisation in both tissue- and bone marrow- derived macrophages (BMDMs). It was revealed that Trib1 does this via modulating levels of C/EBP protein family members, key regulators of macrophage polarisation. Similarly, the data suggest IL-15 may in part play a role in the observations seen. Bone marrow transplantation and high-fat diet feeding exposed Trib1 to be proatherogenic by increasing disease burden in the aorta and aortic sinus of the mice with substantially elevated levels of foam cell macrophages. Microarray analysis of human monocyte-derived macrophages revealed significantly elevated levels of the oxidised LDL receptor ORL1 (LOX-1) and down-regulation of SCARB-1, a receptor involved in reverse cholesterol transport; a finding which was validated in Trib1Tg BMDMs. Trib1Tg ApoE-/- mice also presented with a metabolic phenotype including increased weight, fatty liver, enlarged adipocytes and elevated plasma glucose, which may also implicate the effect of IL-15, since previous studies have shown it to be involved in lipolysis. In conclusion, TRIB1 is a potent regulator of lipid homeostasis, the loss of which promotes inflammation in the liver through Kupffer cell- hepatocyte cross talk. In addition, TRIB1 regulates atherosclerosis, the over-expression of which promotes atherogenesis through elevated oxLDL uptake and subsequent foam cell formation in plaque macrophages. Thus, collectively the study has uncovered previously unreported roles of TRIB1 in vivo that together demonstrate TRIB1 to control distinct aspects of macrophage biology that have local and systemic influence.
Supervisor: Kiss-Toth, Endre ; Francis, Sheila E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.713294  DOI: Not available
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