The effects of atherogenic dyslipidaemia on blood monocyte function

Blood monocytes are heterogeneous effector cells of the innate immune system that can be divided into at least two functionally distinct subpopulations. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterized. The aim of this Ph...

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Main Author: Jackson, William
Other Authors: Woollard, Kevin ; Haskard, Dorian
Published: Imperial College London 2015
Subjects:
Online Access:http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.692313
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spelling ndltd-bl.uk-oai-ethos.bl.uk-6923132017-12-24T15:35:46ZThe effects of atherogenic dyslipidaemia on blood monocyte functionJackson, WilliamWoollard, Kevin ; Haskard, Dorian2015Blood monocytes are heterogeneous effector cells of the innate immune system that can be divided into at least two functionally distinct subpopulations. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterized. The aim of this PhD was to examine the functional response of blood monocyte subpopulations to dyslipidaemia, defined as high levels of plasma VLDL and LDL. Initially in the Ldlr-/- mouse, I demonstrated that monocytes accumulate cytoplasmic neutral lipid vesicles when exposed to high fat diet induced dyslipidaemia. In this model, lipid loaded monocytes exhibit impaired chemotaxis towards peritonitis due to retention of monocytes in the greater omentum. In vitro assays using human monocytes confirmed neutral lipid vesicle accumulation after exposure to LDL or VLDL, via several receptors including CD36. Neutral lipid accumulation did not inhibit other functions including phagocytosis, endothelial adhesion and transendothelial migration, nor did it lead to an overtly pro-inflammatory phenotype. However, lipid loading led to a migratory defect in both monocyte subsets towards C5a and was accompanied by a disruption of cytoskeletal regulation. These cytoskeletal changes included subset specific differences in cell morphology, and an inhibition of RHOA activation and myosin light chain phosphorylation. These data emphasise the functional consequences of blood monocyte lipid accumulation and reveal important implications for treating inflammation, infection and atherogenesis in the context of dyslipidaemia.616.07Imperial College Londonhttp://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.692313http://hdl.handle.net/10044/1/38388Electronic Thesis or Dissertation
collection NDLTD
sources NDLTD
topic 616.07
spellingShingle 616.07
Jackson, William
The effects of atherogenic dyslipidaemia on blood monocyte function
description Blood monocytes are heterogeneous effector cells of the innate immune system that can be divided into at least two functionally distinct subpopulations. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterized. The aim of this PhD was to examine the functional response of blood monocyte subpopulations to dyslipidaemia, defined as high levels of plasma VLDL and LDL. Initially in the Ldlr-/- mouse, I demonstrated that monocytes accumulate cytoplasmic neutral lipid vesicles when exposed to high fat diet induced dyslipidaemia. In this model, lipid loaded monocytes exhibit impaired chemotaxis towards peritonitis due to retention of monocytes in the greater omentum. In vitro assays using human monocytes confirmed neutral lipid vesicle accumulation after exposure to LDL or VLDL, via several receptors including CD36. Neutral lipid accumulation did not inhibit other functions including phagocytosis, endothelial adhesion and transendothelial migration, nor did it lead to an overtly pro-inflammatory phenotype. However, lipid loading led to a migratory defect in both monocyte subsets towards C5a and was accompanied by a disruption of cytoskeletal regulation. These cytoskeletal changes included subset specific differences in cell morphology, and an inhibition of RHOA activation and myosin light chain phosphorylation. These data emphasise the functional consequences of blood monocyte lipid accumulation and reveal important implications for treating inflammation, infection and atherogenesis in the context of dyslipidaemia.
author2 Woollard, Kevin ; Haskard, Dorian
author_facet Woollard, Kevin ; Haskard, Dorian
Jackson, William
author Jackson, William
author_sort Jackson, William
title The effects of atherogenic dyslipidaemia on blood monocyte function
title_short The effects of atherogenic dyslipidaemia on blood monocyte function
title_full The effects of atherogenic dyslipidaemia on blood monocyte function
title_fullStr The effects of atherogenic dyslipidaemia on blood monocyte function
title_full_unstemmed The effects of atherogenic dyslipidaemia on blood monocyte function
title_sort effects of atherogenic dyslipidaemia on blood monocyte function
publisher Imperial College London
publishDate 2015
url http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.692313
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