Abstract
Background and aimsAtherosclerosis is known to be an inflammatory disease and there is increasing evidence that chylomicron remnants (CMR), the lipoproteins which carry dietary fats in the blood, cause macrophage foam cell formation and inflammation. In early atherosclerosis the frequency of activated monocytes in the peripheral circulation is increased, and clearance of CMR from blood may be delayed, however, whether CMR contribute directly to monocyte activation and subsequent egress into the arterial wall has not been established. Here, the contribution of CMR to activation of monocyte pro-inflammatory pathways was assessed using an in vitro model. Methods and resultsPrimary human monocytes and CMR-like particles (CRLP) were used to measure several endpoints of monocyte activation. Treatment with CRLP caused rapid and prolonged generation of reactive oxygen species by monocytes. The pro-inflammatory chemokines MCP-1 and IL-8 were secreted in nanogram quantities by the cells in the absence of CRLP. IL-8 secretion was transiently increased after CRLP treatment, and CRLP maintained secretion in the presence of pharmacological inhibitors of IL-8 production. In contrast, exposure to CRLP significantly reduced MCP-1 secretion. Chemotaxis towards MCP-1 was increased in monocytes pre-exposed to CRLP and was reversed by addition of exogenous MCP-1. ConclusionOur findings indicate that CRLP activate human monocytes and augment their migration in vitro by reducing cellular MCP-1 expression. Our data support the current hypothesis that CMR contribute to the inflammatory milieu of the arterial wall in early atherosclerosis, and suggest that this may reflect direct interaction with circulating blood monocytes.
Highlights
Monocyte activation, triggering their adhesion to the endothelium and subsequent migration into the arterial intima, is an early event in atherogenesis [1e4]
Uptake of oxLDL by monocyte/macrophages is known to play a significant role in atherogenesis by stimulation of the secretion of proinflammatory cytokines, chemokines and other factors [5], but there is considerable evidence to indicate that chylomicron remnants (CMR), the lipoproteins which transport fat of dietary origin from the gut to the liver, are strongly atherogenic [6]
Quantification of the staining density using digital image analysis showed that there was a highly significant increase in the lipid content of CMR-like particles (CRLP)-treated monocytes when compared to cells exposed to the control preparation (P < 0.001, paired Student’s t test) (Figure 1B)
Summary
Monocyte activation, triggering their adhesion to the endothelium and subsequent migration into the arterial intima, is an early event in atherogenesis [1e4]. Lipids from food are absorbed in the gut and secreted into lymph in large, triacylglycerol (TG)-rich lipoproteins called chylomicrons which pass into the blood via the thoracic duct. They undergo rapid lipolysis, a process that removes some of their TG and forms the smaller CMR which deliver the remaining TG, cholesterol and other lipids to the liver [7]. Atherosclerosis is known to be an inflammatory disease and there is increasing evidence that chylomicron remnants (CMR), the lipoproteins which carry dietary fats in the blood, cause macrophage foam cell formation and inflammation.
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