Abstract
Blood monocytes are heterogeneous effector cells of the innate immune system. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterised. Our aim was to examine the functional effect of hyperlipidaemia on blood monocytes. In the Ldlr−/− mouse monocytes rapidly accumulate cytoplasmic neutral lipid vesicles during hyperlipidaemia. Functional analysis in vivo revealed impaired monocyte chemotaxis towards peritonitis following high fat diet 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. Neutral lipid accumulation did not inhibit phagocytosis, endothelial adhesion, intravascular crawling and transmigration. However, lipid loading led to a migratory defect towards C5a and disruption of cytoskeletal rearrangement, including an inhibition of RHOA signaling. These data demonstrate distinct effects of hyperlipidaemia on the chemotaxis and cytoskeletal regulation of monocyte subpopulations. These data emphasise the functional consequences of blood monocyte lipid accumulation and reveal important implications for treating inflammation, infection and atherosclerosis in the context of dyslipidaemia.
Highlights
Blood monocytes are heterogeneous effector cells of the innate immune system
We aimed to characterise the interactions of monocyte subsets (GR1hi and GR1low) with blood lipoproteins in the hyperlipidaemic Ldlr−/− mouse with raised plasma VLDL and LDL28
Monocyte CD11b levels decreased on both subpopulations on high fat diet (HFD) (Supplemental Fig. 1a), while MHC-II (I-A) and GR1 expression did not change vesicle median fluorescence intensity (MFI) (20–25 cells per subset) in HFD only
Summary
Blood monocytes are heterogeneous effector cells of the innate immune system. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterised. Lipid loading led to a migratory defect towards C5a and disruption of cytoskeletal rearrangement, including an inhibition of RHOA signaling These data demonstrate distinct effects of hyperlipidaemia on the chemotaxis and cytoskeletal regulation of monocyte subpopulations. These data emphasise the functional consequences of blood monocyte lipid accumulation and reveal important implications for treating inflammation, infection and atherosclerosis in the context of dyslipidaemia. Experimental models of dyslipidemia with elevated levels of VLDL and LDL lead to immune suppression during infection with Staphylococcus aureus, Mycobacterium tuberculosis, Candida albicans and Listeria monocytogenes, resulting in increased pathogen load and defective phagocytosis[13,14,15,16]. Given the increasing disparity between monocytes and tissue macrophages[1] and the distinct kinematic phenotypes of monocyte subpopulations in homeostatic and inflammatory conditions during atherosclerosis[25], further investigation was warranted into the effects of dyslipidaemia on monocyte migration during inflammation independent of cardiovascular disease
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