CD11c/CD18 Expression Is Upregulated on Blood Monocytes During Hypertriglyceridemia and Enhances Adhesion to Vascular Cell Adhesion Molecule-1

Gower, R. Michael; Wu, Huaizhu; Foster, Gregory D.; Devaraj, Sridevi; Jialal, Ishwarlal; Ballantyne, Christie M.; Knowlton, Anne A; Simon, Scott I.

doi:10.1161/atvbaha.110.215434

Cited by 142 publications

(158 citation statements)

References 40 publications

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“…Atherosclerosis presents as a chronic inflammatory disease but has also been characterized as a postprandial phenomenon, affected not only by a heightened state of metabolic-induced inflammation but also exacerbated by events such as a single high-fat meal (33,42) and promoted by repetitive exposure to transiently elevated lipoproteins and associated endothelial dysfunction (17,36,39,44). The results of the present study, together with our previous reports on the inflammatory nature of TGRL, are consistent with repeated episodes of enhanced inflammation in response to dietary factors that can have long-term cumulative consequences (33,45).…”

Section: Discussionmentioning

confidence: 99%

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

DeVerse

Sandhu

Mendoza

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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DeVerse JS, Sandhu AS, Mendoza N, Edwards CM, Sun C, Simon SI, Passerini AG. Shear stress modulates VCAM-1 expression in response to TNF-␣ and dietary lipids via interferon regulatory factor-1 in cultured endothelium. Am J Physiol Heart Circ Physiol 305: H1149-H1157, 2013. First published August 9, 2013; doi:10.1152/ajpheart.00311.2013.-Dyslipidemia is a primary risk factor for cardiovascular disease, but the specific mechanisms that determine the localization of atherosclerotic plaques in arteries are not well defined. Triglyceride-rich lipoproteins (TGRL) isolated from human plasma after a high-fat meal modulate TNF-␣-induced VCAM-1 expression in cultured human aortic endothelial cells (HAECs) via an interferon regulatory factor (IRF)-1-dependent transcriptional mechanism. We examined whether fluid shear stress acts as a mediator of IRF-1-dependent VCAM-1 expression in response to cytokine and dietary lipids. IRF-1 and VCAM-1 were examined by immunofluorescence in TNF-␣-stimulated HAEC monolayers exposed to TGRL and a linear gradient of shear stress ranging from 0 to 16 dyn/cm 2 in a microfluidic device. Shear stress alone modulated TNF-␣-induced VCAM-1 expression, eliciting a 150% increase at low shear stress (2 dyn/cm 2 ) and a 70% decrease at high shear stress (12 dyn/cm 2 ) relative to static. These differences correlated with a 60% increase in IRF-1 expression under low shear stress and a 40% decrease under high shear stress. The addition of TGRL along with cytokine activated a fourfold increase in VCAM-1 expression and a twofold increase in IRF-1 expression. The combined effect of shear stress and TGRL on the upregulation of membrane VCAM-1 was abolished by transfection of HAECs with IRF-1-specific small interfering RNA. In a healthy swine model, elevated levels of endothelial IRF-1 were also observed within atherosusceptible regions of the aorta by Western blot analysis and immunohistochemistry, implicating arterial hemodynamics in the regulation of IRF-1 expression. These data demonstrate direct roles for fluid shear stress and postprandial TGRL from human serum in the regulation of IRF-1 expression and downstream inflammatory responses in HAECs.atherosclerosis; hemodynamics; hypertriglyceridemia; endothelial dysfunction; inflammation; vascular cell adhesion molecule 1; tumor necrosis factor-␣ ATHEROSCLEROSIS is a multifactorial disease characterized by the focal accumulation of lipid-rich plaques at arterial sites that correlate strongly with regions of disturbed blood flow. Diets high in saturated and nonesterified fats contribute to a state of metabolic dysregulation that is associated with chronic lowgrade inflammation and activation of stress responses that accelerate the progression of atherosclerosis (18,21). Elevated levels of circulating lipoproteins and cytokines, such as TNF-␣, contribute to inflammatory responses that culminate in the preferential recruitment of leukocytes to the endothelium via the upregulation of cell adhesion molecules, including VCAM-1 (24). Despite the recognition that...

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Section: Discussionmentioning

confidence: 99%

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

DeVerse

Sandhu

Mendoza

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Monocytes were identified as CD45 hi CD115 hi and further subdivided into Ly6-C hi and Ly6-C lo ; neutrophils were identified as CD45 hi CD115 lo Ly6-C/G hi (Gr-1). CD11b, CD11c, VLA-4 MFI and percent CD62L + was measured on Ly6-C hi monocytes as a marker of activation (38,62).…”

Section: Flow Cytometrymentioning

confidence: 99%

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

Murphy¹,

Akhtari²,

Tolani³

et al. 2011

J. Clin. Invest.

443

532

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Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe -/-mice fed a chow or Western-type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1 -/-mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1-and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe -/-mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.

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“…Although low-density lipoprotein (LDL) is a clinically important marker used to predict onset of CAD, serum triglyceride level and its content in triglyceride-rich lipoproteins (TGRLs) are emerging as metabolically driven biomarkers for predicting acute cardiovascular events (3). In this context, TGRLs containing apolipoprotein C-III remain in circulation due to diminished hepatic clearance (4), are readily taken up by monocytes in blood (5), and are endocytosed by endothelial cells, resulting in vascular cell adhesion molecule-1 (VCAM-1) up-regulation and enhanced recruitment of monocytes in shear flow (6). Activation of monocytes and their increased influx to coronary arteries correlate with plaque progression and instability, and inflammatory monocytes contribute to infarct size (7).…”

Section: Cd16mentioning

confidence: 99%

“…We have identified CD11c/CD18 as a functional receptor expressed on an inflammatory subset of monocytes (5). CD11c/CD18 is upregulated in apolipoprotein E-deficient mice made dyslipidemic on a high-fat diet, and genetic depletion of CD11c abrogated the development of atherosclerosis (12).…”

Section: Cd16mentioning

confidence: 99%

On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction

Foster¹,

Gower²,

Stanhope

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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, and each may play distinct roles during atherogenesis and myocardial infarction. We studied a range of subjects that included otherwise healthy patients with elevated serum triglyceride levels to patients presenting with acute myocardial infarction. Our objective was to correlate an individual's risk with the activation state of each monocyte subset as a function of changes in adhesion receptor expression using flow cytometric quantitation of integrins and L-selectin membrane expression. A microfluidic-based laboratory-on-a-chip was developed to quantify the adhesion efficiency of monocytes sheared in whole blood on vascular cell adhesion molecule-1, while characterizing adhesion receptor expression and topography on captured monocytes. CD14 ++ CD16+ monocytes adhered with sevenfold higher efficiency than other subsets, and in patients with myocardial infarction the capture efficiency of this subset was double that for healthy subjects. In patients with hypertriglyceridemia, this increase in monocyte adhesion was attributable to CD14 ++ CD16+ uptake of triglyceride-rich lipoproteins and subsequent signaling via a Phospholipase C-dependent mechanism to increase CD11c expression, very late antigen-4 function, and integrin coclustering within focal adhesive sites on vascular cell adhesion molecule-1. In summary, we introduce a unique laboratory-on-a-chip method for quantifying the activation state of monocyte subsets. These experiments reveal that CD11c/CD18 is an inducible integrin whose expression correlates with a monocyte inflammatory state in subjects at risk for atherogenesis and in patients with myocardial infarction.B2-integrin | cell arrest | shear flow

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CD11c/CD18 Expression Is Upregulated on Blood Monocytes During Hypertriglyceridemia and Enhances Adhesion to Vascular Cell Adhesion Molecule-1

Cited by 142 publications

References 40 publications

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction

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