Investigating the causes and consequences of miR-34a dysregulation in rheumatoid arthiritis

Tange, Clare Elizabeth (2015) Investigating the causes and consequences of miR-34a dysregulation in rheumatoid arthiritis. PhD thesis, University of Glasgow.

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Abstract

Rheumatoid arthritis (RA) is a chronic, inflammatory disorder, whereby synovial inflammation ultimately results in joint destruction. Although the joints are the main target tissues affected, RA is also associated with a number of co-morbidities - such as cardiovascular disease. A key cell type involved in the perpetuation of disease pathogenesis is the macrophage, but the mechanisms underlying inflammatory gene expression in these cells are not fully understood. One fascinating and rather novel area of research that could provide insights into the activation of macrophages in RA comprises the biology of microRNA. These small, non-coding RNA molecules are implicated in the post-transcriptional regulation of gene expression. Here, we show that the expression of one particular microRNA, miR-34a, is increased in synovial fluid CD14+ cells compared to matched peripheral blood cells from RA patients. We have demonstrated that miR-34a expression is increased in synovial tissues from RA patients compared to osteoarthritis comparators, and that a proportion of these miR-34a positive cells are CD68+ macrophages. Of particular interest, miR-34a was also up-regulated in peripheral blood CD14+ cells isolated from multiple drug-resistant RA patients compared to healthy controls. Using over and under-expression methodologies we were able to demonstrate that miR-34a over-expression reduces toll like receptor-induced cytokine production by macrophages, while miR-34a inhibition enhances cytokine production. The altered cytokine activities included TNFα and IL-6 that are both critically linked to disease pathogenesis, therefore we propose that miR-34a over-expression in RA macrophages represents a failed attempt to attenuate on-going inflammation. To further explore the mechanism of miR-34a action, a microarray was performed to investigate transcripts that were regulated in response to miR-34a over-expression in monocytes. This study uncovered several pathways, including interferon, metallothionein and chemokine pathways, wherein many members were down-regulated upon miR-34a over-expression. Future work will therefore aim to dissect the role of these pathways, and their relevance to miR-34a regulated macrophage and dendritic cell biology, and thus to the chronicity of synovitis.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Rheumatoid Arthritis, microRNA, miRNA, macrophage
Subjects: Q Science > Q Science (General)
Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Funder's Name: UNSPECIFIED
Supervisor's Name: McInnes, Prof. Iain and Kurowska-Stolarska, Dr. Mariola
Date of Award: 2015
Embargo Date: 7 January 2018
Depositing User: Miss Clare Elizabeth Tange
Unique ID: glathesis:2015-5880
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 08 Jan 2015 10:09
Last Modified: 08 Jan 2015 10:09
URI: http://theses.gla.ac.uk/id/eprint/5880

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