Very-low and low-density lipoproteins induce neutral lipid accumulation and impair migration in monocyte subsets

Jackson, William D.; Weinrich, Tobias W.; Woollard, Kevin J.

doi:10.1038/srep20038

Cited by 27 publications

(33 citation statements)

References 54 publications

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“…Previous studies have reported that human and mouse NCM do not ingest native LDL (LDL) or very low-density lipoproteins (VLDL) as much as do CM 32 , so we tested whether blood NCM would preferentially uptake modified forms of LDL. CX 3 CR1 gfp/+ CCR2 rfp/+ ApoE −/− mice were injected intravenously with fluorescently-labeled LDL, native LDL protected from oxidation by BHT (BHT-LDL), minimally modified LDL (mmLDL) 33,34 and copper-oxidized LDL (OxLDL).…”

Section: Resultsmentioning

confidence: 99%

Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

Marcovecchio

Thomas

Mikulski

et al. 2017

ATVB

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Objective Nonclassical monocytes function to maintain vascular homeostasis by crawling or patrolling along the vessel wall. This subset of monocytes responds to viruses, tumor cells, and other pathogens to aid in protection of the host. In this study, we wished to determine how early atherogenesis impacts nonclassical monocyte patrolling in the vasculature. Approach and Results To study the role of nonclassical monocytes in early atherogenesis, we quantified the patrolling behaviors of nonclassical monocytes in ApoE−/− and C57Bl/6J mice fed a Western diet. Using intravital imaging, we found that nonclassical monocytes from Western diet fed mice display a 4-fold increase in patrolling activity within large peripheral blood vessels. Both human and mouse nonclassical monocytes preferentially engulfed oxidized LDL in the vasculature, and we observed that oxidized LDL selectively induced nonclassical monocyte patrolling in vivo. Induction of patrolling during early atherogenesis required scavenger receptor CD36, as CD36−/− mice revealed a significant reduction in patrolling activity along the femoral vasculature. Mechanistically, we found that CD36-regulated patrolling was mediated by a Src family kinase (SFK) through DAP12 adaptor protein. Conclusions Our studies show a novel pathway for induction of nonclassical monocyte patrolling along the vascular wall during early atherogenesis. Mice fed a Western diet showed increased nonclassical monocyte patrolling activity with a concurrent increase in SFK phosphorylation. This patrolling activity was lost in the absence of either CD36 or Dap12. These data suggest that nonclassical monocytes function in an atheroprotective manner through sensing and responding to oxidized lipoprotein moieties via scavenger receptor engagement during early atherogenesis.

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Section: Resultsmentioning

confidence: 99%

Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

Marcovecchio

Thomas

Mikulski

et al. 2017

ATVB

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“…This important experiment also showed that monocytes accumulate in waves and implied that there is little phagocytosis of older macrophages by newly infiltrating cells (95). Lipid loading extends beyond macrophages; monocytes have been shown to accumulate lipid droplets, especially if they encounter TRLs, which in turn impair their migration (96). Our recent findings suggest that diabetes increases the ensnaring of pro-atherogenic particles containing APOB, APOC3, and APOE (indicating that they might be TRLs or RLPs derived from TRLs) in the artery wall and that this contributes to accelerated atherosclerosis (19).…”

Section: Aberrant Lipid Metabolism In Monocytes and Macrophages Is A mentioning

confidence: 96%

Monocytes and Macrophages as Protagonists in Vascular Complications of Diabetes

Kanter

Hsu

Bornfeldt

2020

Front. Cardiovasc. Med.

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With the increasing prevalence of diabetes worldwide, vascular complications of diabetes are also on the rise. Diabetes results in an increased risk of macrovascular complications, with atherosclerotic cardiovascular disease (CVD) being the leading cause of death in adults with diabetes. The exact mechanisms for how diabetes promotes CVD risk are still unclear, although it is evident that monocytes and macrophages are key players in all stages of atherosclerosis both in the absence and presence of diabetes, and that phenotypes of these cells are altered by the diabetic environment. Evidence suggests that at least five pro-atherogenic mechanisms involving monocytes and macrophages contribute to the accelerated atherosclerotic lesion progression and hampered lesion regression associated with diabetes. These changes include (1) increased monocyte recruitment to lesions; (2) increased inflammatory activation; (3) altered macrophage lipid accumulation and metabolism; (4) increased macrophage cell death; and (5) reduced efferocytosis. Monocyte and macrophage phenotypes and mechanisms have been revealed mostly by different animal models of diabetes. The roles of specific changes in monocytes and macrophages in humans with diabetes remain largely unknown. There is an ongoing debate on whether the changes in monocytes and macrophages are caused by altered glucose levels, insulin deficiency or insulin resistance, lipid abnormalities, or combinations of these factors. Current research in humans and mouse models suggests that reduced clearance of triglyceride-rich lipoproteins and their remnants is one important mechanism whereby diabetes adversely affects macrophages and promotes atherosclerosis and CVD risk. Although monocytes and macrophages readily respond to the diabetic environment and can be seen as protagonists in diabetes-accelerated atherosclerosis, they are likely not instigators of the increased CVD risk.

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“…Furthermore, very low-and low-density lipoproteins (VLDL and LDL, respectively) cause neutral lipid accumulation in human monocytes and mouse peritoneal macrophages, impairing their migratory abilities due to blunting of RHOA activation, and consequently of cytoskeletal rearrangements. 86 Oxidized LDL inhibits macrophage migration by interacting with the scavenger receptor CD36, which triggers a pathway that results in RAC1 activation and RAC-mediated inhibition of MLC kinase. This leads to MLC dephosphorylation and retraction of the front end lamellipodia, thus resulting in loss of cell polarity.…”

Section: Dyslipidemia and Immune Cell Motilitymentioning

confidence: 99%

Implications of cellular metabolism for immune cell migration

Guak

Krawczyk

2020

Immunology

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Cell migration is an essential, energetically demanding process in immunity. Immune cells navigate the body via chemokines and other immune mediators, which are altered under inflammatory conditions of injury or infection. Several factors determine the migratory abilities of different types of immune cells in diverse contexts, including the precise coordination of cytoskeletal remodelling, the expression of specific chemokine receptors and integrins, and environmental conditions. In this review, we present an overview of recent advances in our understanding of the relationship of each of these factors with cellular metabolism, with a focus on the spatial organization of glycolysis and mitochondria, reciprocal regulation of chemokine receptors and the influence of environmental changes.

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Very-low and low-density lipoproteins induce neutral lipid accumulation and impair migration in monocyte subsets

Cited by 27 publications

References 54 publications

Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

Monocytes and Macrophages as Protagonists in Vascular Complications of Diabetes

Implications of cellular metabolism for immune cell migration

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