Abstract
SummaryMonocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. However, their response to hyperlipidemia remains poorly understood. Here, we report that in the presence of elevated levels of triglyceride-rich lipoproteins, induced by administration of poloxamer 407, the blood numbers of non-classical Ly6C/Gr1low monocytes drop, while the number of bone marrow progenitors remains similar. We observed an increased crawling and retention of the Gr1low monocytes at the endothelial interface and a marked accumulation of CD68+ macrophages in several organs. Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1low monocyte depletion involved a pertussis-toxin-sensitive receptor axis. Collectively, these findings demonstrate that a triglyceride-rich environment can alter blood monocyte distribution, promoting the extravasation of Gr1low cells. The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells.
Highlights
Marked elevations in triglyceride-rich lipoprotein (TGRL) levels are observed in individuals with rare genetic disorders such as familial lipoprotein lipase deficiency (Benlian et al, 1996) and when a common genetic disorder occurs in association with an acquired secondary form of hypertriglyceridemia such as diabetes or alcohol consumption (Pejic and Lee, 2006)
Elevated TGRL Levels Alter Blood Monocyte Subset Distribution To mimic the increased TGRL levels observed in many patients with metabolic disorders, we used the poloxamer 407 (P-407)induced model of dyslipidemia (Johnston, 2004)
As previously reported (Johnston, 2004), we found that administration of P-407 (0.5 g/kg every second day) to B6 mice for 28 days resulted in an average plasma triglyceride (TG) concentration of 2,691.2 ± 501.8 mg/dl compared with 80.2 ± 6.26 mg/dl in PBS-treated controls and a modest increase in plasma cholesterol (CHOL)
Summary
Marked elevations in triglyceride-rich lipoprotein (TGRL) levels are observed in individuals with rare genetic disorders such as familial lipoprotein lipase deficiency (Benlian et al, 1996) and when a common genetic disorder occurs in association with an acquired secondary form of hypertriglyceridemia such as diabetes or alcohol consumption (Pejic and Lee, 2006). Elevated TGRL levels are thought to contribute to the increased risk of cardiovascular complications observed in all these conditions (Benlian et al, 1996; Bruce, 2005), the pathogenic impact of an abnormal TGRL profile remains poorly understood. The notion of toxic and inflammatory effects of lipid metabolites has been supported by an extensive literature using murine models of hyperlipidemia such as strains genetically deficient in either the low-density lipoprotein receptor (LDLR) or apolipoprotein E (ApoE). These models replicate human hypercholesterolemic states and the associated inflammatory response, but they do not recapitulate triglyceride-rich dyslipidemia. Reports of postprandial activation of monocytes from acute changes in TGRLs (Gower et al, 2011) suggest that these cells may be important in the handling of circulating lipids
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