Inflammatory Chemokines in Atherosclerosis

Gencer, Selin; Evans, Bryce R.; Vorst, Emiel P. C. van der; Döring, Yvonne

doi:10.3390/cells10020226

Cited by 109 publications

(89 citation statements)

References 150 publications

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“…It is well established that vascular endothelial cell activation with TNFα triggers production of a wide array of leukocyte-recruiting chemokines. Among these, MCP-1/CCL2 and RANTES/CCL5 have been shown to play a critical role in mononuclear leukocyte arrest and participate in the progression of atherosclerotic lesions [29,30]. In the present study, CITCO inhibited TNFα-elicited MCP-1/CCL2 and RANTES/CCL5 release, an effect blunted in cells lacking CAR, suggesting that CAR activation decreases leukocyte arrest by inhibiting chemokine generation and release.…”

Section: Discussionsupporting

confidence: 54%

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium

López-Riera

Ortega

Hueso

et al. 2021

IJMS

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Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes.

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Section: Discussionsupporting

confidence: 54%

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium

López-Riera

Ortega

Hueso

et al. 2021

IJMS

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“…In the peripheral blood of patients with cardiovascular diseases a higher share of effector memory T cells (TEM cells or TEM) characterized as CD3 + CD4 + CD45RA − CD45RO + CCR7 − were found, which relate to the degree of atherosclerotic lesions in the coronary and brain carotid regions [39]. In comparison with these results, other studies have demonstrated a CCR7 − T cell elevation in patients with coronary artery disease [40], and T cell memory increase in patients with subclinical carotid atherosclerosis [41].…”

Section: Circulating T Cell Subpopulationsmentioning

confidence: 82%

Immunity in Atherosclerosis: Focusing on T and B Cells

Poznyak

Bezsonov

Popkova

et al. 2021

IJMS

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Atherosclerosis is the major cause of the development of cardiovascular disease, which, in turn, is one of the leading causes of mortality worldwide. From the point of view of pathogenesis, atherosclerosis is an extremely complex disease. A huge variety of processes, such as violation of mitophagy, oxidative stress, damage to the endothelium, and others, are involved in atherogenesis; however, the main components of atherogenesis are considered to be inflammation and alterations of lipid metabolism. In this review, we want to focus on inflammation, and more specifically on the cellular elements of adaptive immunity, T and B cells. It is known that various T cells are widely represented directly in atherosclerotic plaques, while B cells can be found, for example, in the adventitia layer. Of course, such widespread and well-studied cells have attracted attention as potential therapeutic targets for the treatment of atherosclerosis. Various approaches have been developed and tested for their efficacy.

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“…Given that macrophages-related inflammation and lipid accumulation play essential roles in AS ( Poznyak et al, 2020 ; Gencer et al, 2021 ), we further explored whether TDP43 is involved in these biological processes. To verify this hypothesis, TDP43 specific siRNAs were synthesized.…”

Section: Resultsmentioning

confidence: 99%

TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages

Huangfu

Wang

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveAtherosclerosis (AS), characterized by cholesterol overloaded-macrophages accumulation and plaque formation in blood vessels, is the major cause of cardiovascular disease. Transactive response DNA-binding protein∼43 kDa (TDP43) has recently been identified as an independent driver of neurodegenerative diseases through triggering inflammatory response. This study investigated whether TDP43 is involved in AS development, especially in macrophages-mediated-foam cell formation and inflammatory responses.MethodsTransactive response DNA-binding protein∼43 kDa expressions in oxidized low-density lipoprotein (oxLDL)-treated macrophages and peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) were detected by real time-polymerase chain reaction (RT-PCR), Western blot, and immunofluorescence. Gene gain or loss of function was used to investigate the effects of TDP43 on macrophages-mediated lipid untake and inflammation with ELISA, protein immunoprecipitation, RT-PCR, Western blot, and immunofluorescence. Macrophage TDP43 specific knockout mice with ApoE–/– background were fed with western diet for 12 weeks to establish AS model, and used to explore the role of TDP43 on AS progression.ResultsTransactive response DNA-binding protein∼43 kDa expression increases in oxLDL-treated macrophages and PBMCs from patients with CAD. Furthermore, we find that TDP43 promotes activation of NF-κB to increase inflammatory factor expression in macrophages through triggering mitochondrial DNA release to activate cGAS-STING signaling. Moreover, TDP43 strengthens lipid uptake of macrophages through regulating β-catenin and PPAR-γ complex to promote scavenger receptor gene CD36 transcription. Finally, using macrophage TDP43 specific knockout mice with ApoE–/– background fed with western diet for 12 weeks to establish AS model, we find that specific knockout of TDP43 in macrophages obviously alleviates western diet-induced AS progression in mice.ConclusionsTransactive response DNA-binding protein∼43 kDa exacerbates atherosclerosis progression by promoting inflammation and lipid uptake of macrophages, suggesting TDP43 as a potential target for developing atherosclerotic drug.

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Inflammatory Chemokines in Atherosclerosis

Cited by 109 publications

References 150 publications

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium

Immunity in Atherosclerosis: Focusing on T and B Cells

TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages

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