Toll-like receptor-dependent lipid body formation in macrophage foam cell formation

Nicolaou, Giovanna; Erridge, Clett

doi:10.1097/mol.0b013e32833cacd5

Cited by 29 publications

(29 citation statements)

References 49 publications

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“…Previous studies by our and other laboratories have shown that the activation of macrophages with LPS and other TLR activators increases macrophage TG accumulation ( 29,30 ). We therefore next examined the effect of have failed to demonstrate that niacin therapy when added to statins reduces cardiovascular disease events (34)(35)(36).…”

Section: Downloaded Frommentioning

confidence: 99%

Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages

Feingold

Moser

Shigenaga

et al. 2014

Journal of Lipid Research

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Section: Downloaded Frommentioning

confidence: 99%

Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages

Feingold

Moser

Shigenaga

et al. 2014

Journal of Lipid Research

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“…21,43,[47][48][49][50][51] First, TLRs induce foam cell formation by increasing the uptake of lipoproteins and the storage of lipid (via increases in CD36, AP2, fatty acid-binding proteins, MyD88-adaptor-like, adipose differentiation-related protein, lipin 1, glycerol-3-phosphate acyltransferase 3, and diacylglycerol O-acyltransferase 2). 52,53 Second, TLRs decrease the delivery of cholesterol macrophages to high-density lipoprotein (HDL), the first step in reverse cholesterol transport (via decreases in macrophages ATP-binding cassette transporter subfamily A (ABCA)-1, ATP-binding cassette transporter subfamily G, scavenger receptor class B, member 1/CD36 antigen-like 1, and apolipoprotein E). [54][55][56] The HIV Nef gene is also known to activate macrophages, in part, by increasing CD36, and to facilitate the transformation of macrophages to foam cells.…”

Section: Monocyte Migration and Differentiation Of Macrophage And Foamentioning

confidence: 99%

HIV, Inflammation, and Calcium in Atherosclerosis

Shrestha

Irvin

Grünfeld

et al. 2014

ATVB

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“…TLR4 is the bestcharacterized of the TLR receptors, and was previously reported to be activated by heme in human embryonic kidney-293 or macrophage cell lines (18,22). Thus, to determine whether NFkB and HIF activation in our system was dependent on a TLR4-signaling pathway, HMECs-1 were treated with HbFe 21 , HbFe 31 , HbFe 41 , or LPS (as a positive control) in the presence or absence of a TLR4 inhibitor, TAK-242.…”

Section: Tlr4 Inhibitionmentioning

confidence: 99%

“…TLR receptors are expressed in many cell types, including the vascular endothelium, and play a key role in the innate immune response (17)(18)(19)(20). Nearly all TLRs activate the myeloid differentiation primary response gene-88 (MyD88) pathway that regulates NF-kB (19).…”

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confidence: 99%

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Lisk¹,

Kominsky²,

Ehrentraut³

et al. 2013

Am J Respir Cell Mol Biol

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The release of hemoglobin (Hb) with hemolysis causes vascular dysfunction. New evidence implicates Hb-induced NF-kB and hypoxia inducible factor (HIF) activation, which may be under the control of a Toll-like receptor (TLR)-signaling pathway. Nearly all TLR-signaling pathways activate the myeloid differentiation primary response gene-88 (MyD88) that regulates NF-kB. We hypothesized that the differing transition states of Hb influence endothelial cell permeability via NF-kB activation and HIF regulation through a MyD88-dependent pathway. In cultured human dermal microvascular endothelial cells (HMECs-1), we examined the effects of Hb in the ferrous (HbFe 21 ), ferric (HbFe 31 ), and ferryl (HbFe 41 ) transition states on NF-kB and HIF activity, HIF-1a and HIF-2a mRNA upregulation, and monolayer permeability, in the presence or absence of TLR4, MyD88, NF-kB, or HIF inhibition, as well as superoxide dismutase (SOD) and catalase. Our data showed that cell-free Hb, in each transition state, induced NF-kB and HIF activity, up-regulated HIF-1a and HIF-2a mRNA, and increased HMEC-1 permeability. The blockade of either MyD88 or NF-kB, but not TLR4, attenuated Hb-induced HIF activity, the up-regulation HIF-1 and HIF-2a mRNA, and HMEC-1 permeability. The inhibition of HIF activity exerted less of an effect on Hb-induced monolayer permeability. Moreover, SOD and catalase attenuated NF-kB, HIF activity, and monolayer permeability. Our results demonstrate that Hb-induced NF-kB and HIF are regulated by two mechanisms, either MyD88 activation or Hb transition state-induced ROS formation, that influence HMEC-1 permeability.Keywords: hemolytic disease; NF-kB; Toll-like receptors; MyD88; sicklecell disease Humans with chronic vascular inflammation and vasoconstriction develop progressive endothelial dysfunction and vascular diseases (e.g., pulmonary arterial hypertension, atherosclerosis, and sickle-cell disease) (1, 2). Vascular diseases develop in the face of chronic hemolysis, as occurs with hemoglobinopathies (including sickle-cell disease), or with the intermittent release of low to moderate levels of plasma-free hemoglobin (Hb), as may be seen in atherosclerosis with intraplaque hemorrhage.Low to moderate levels of plasma-free Hb may, in part, mediate these diseases (1-4). However, studies to date have not fully addressed the complete mechanisms responsible for Hb-induced vascular dysfunction.The a 2 b 2 tetramers of Hb transition safely and effectively between the relaxed (oxy) and tense (deoxy) conformational states, and the oxidation of Hb is controlled by red blood cell catalase, superoxide dismutase (SOD), and ferric Hb reductase. However, after their release from the red blood cell, Hb tetramers and dimers can be oxidized from ferrous (HbFe 21 ) to ferric (HbFe 31 ) (3-5). In theory, HbFe 31 in local tissue environments may react with hydrogen peroxide (H 2 O 2 ) to transition between the ferryl (HbFe 41 ) and HbFe 31 states, leading to heme release, globin chain denaturation, and globin chain crosslinking (4, 5). Oxid...

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Toll-like receptor-dependent lipid body formation in macrophage foam cell formation

Abstract: TLR stimulation promotes the accumulation of lipid bodies in macrophages and consequently foam cell formation. The pathways responsible for these processes may constitute novel therapeutic targets for atherosclerosis.

Cited by 29 publications

References 49 publications

Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages

Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages

HIV, Inflammation, and Calcium in Atherosclerosis

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

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