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Microrna regulation of macrophage phenotype in peritoneal fibrosis

Jenkins, Robert, Liao, Chia-Te, Wallace, Leah, Bowen, Timothy, Topley, Nicholas, Taylor, Philip and Fraser, Donald 2015. Microrna regulation of macrophage phenotype in peritoneal fibrosis. Nephrology Dialysis Transplantation 30 (iii262) 10.1093/ndt/gfv180.15

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Abstract

Introduction and Aims: Peritoneal fibrosis is a major cause of treatment failure in peritoneal dialysis, which is linked to repeat episodes of infection-driven peritoneal inflammation. Macrophages are a heterogeneous population of immune cells essential for immune surveillance, response to infection and the resolution of inflammation. Distinct subpopulations of macrophages are implicated in tissue repair and fibrosis. Recent data from our group defines distinct origin, function and transcriptional control of discrete macrophage subsets within the peritoneal cavity, namely tissue resident (homeostatic) and inflammatory. microRNAs are post-transcriptional regulators of gene expression that play fundamental roles in regulation of cellular phenotype. However, the role of microRNAs has not been examined in this context. Aim: To investigate microRNA regulation of macrophage phenotype in the context of peritoneal fibrosis. Methods: An in vivo study of microRNA regulation of tissue resident and inflammatory macrophage phenotype in an established murine model of peritoneal fibrosis. Results: A single episode of acute peritoneal inflammation is self-limiting with restoration of tissue homeostasis, whereas repeat episodes initiate the development of fibrosis. In response to acute inflammation two distinct macrophage lineage branches are evident, M2-like tissue resident macrophages (F4/80highCD11bhighTIM4-/+) and bone marrow derived inflammatory macrophages (F4/80+CD11b+TIM4-). We have employed both hybridization arrays and next generation sequencing to identify differential expression of microRNAs in resident and inflammatory macrophages in response to single and repeat episodes of acute inflammation. Analysis of the microRNA expression data, together with in silico prediction of putative mRNA targets, has identified several microRNAs implicated in regulation of macrophage phenotype. In order to determine the precise functions of these microRNAs we are developing both constitutive and condition lentiviral vectors for 1) microRNA expression and 2) microRNA repression based on the Tough Decoy (TuD) principle. Conclusions: Macrophages are a heterogeneous population of cells tailored by their microenvironment and tissue-specific functions. Delineating the post-transcription regulation of macrophage heterogeneity has important therapeutic applications in peritoneal fibrosis.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Oxford University Press
ISSN: 0931-0509
Last Modified: 27 Nov 2017 22:17
URI: http://orca.cf.ac.uk/id/eprint/94168

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