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 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.Open Acces