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Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets

https://doi.org/10.1016/j.cytogfr.2015.04.003Get rights and content
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Abstract

Atherosclerosis, a chronic inflammatory disorder of the arteries, is responsible for most deaths in westernized societies with numbers increasing at a marked rate in developing countries. The disease is initiated by the activation of the endothelium by various risk factors leading to chemokine-mediated recruitment of immune cells. The uptake of modified lipoproteins by macrophages along with defective cholesterol efflux gives rise to foam cells associated with the fatty streak in the early phase of the disease. As the disease progresses, complex fibrotic plaques are produced as a result of lysis of foam cells, migration and proliferation of vascular smooth muscle cells and continued inflammatory response. Such plaques are stabilized by the extracellular matrix produced by smooth muscle cells and destabilized by matrix metalloproteinase from macrophages. Rupture of unstable plaques and subsequent thrombosis leads to clinical complications such as myocardial infarction. Cytokines are involved in all stages of atherosclerosis and have a profound influence on the pathogenesis of this disease. This review will describe our current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions.

Keywords

Atherosclerosis
Cytokines
Chemokines
Inflammation
Therapeutic avenues

Abbreviations

ABC
ATP-binding cassette
ACAT-1
acyl-CoA acyl transferase-1
ADRP
adipocyte differentiation related protein
Apo
apolipoprotein
BMT
bone marrow transplantation
CANTOS
Canakinumab Anti-inflammatory Thrombosis Outcomes Study
CIRT
Cardiovascular Inflammation Reduction Trial
CCR2
CC-chemokine receptor-2
CR
chemokine receptor
CVD
cardiovascular disease
CSF
colony-stimulating factor
DCs
dendritic cells
ECs
endothelial cells
ECM
extracellular matrix
eNOS
endothelial nitric oxide synthase
ER
endoplasmic reticulum
ERK
extracellular signal-regulated kinase
Fn14
fibroblast growth factor-inducible 14
G-CSF
granulocyte colony-stimulating factor
GDF-15
growth differentiation factor-15
GM-CSF
granulocyte macrophage colony-stimulating factor
ICAM-1
intercellular adhesion molecule-1
IFN
interferon
IL
interleukin
IL-18BP
IL-18 binding protein
IL-1RA
IL-1 receptor antagonist
LDL
low-density lipoprotein
LDLr
low-density lipoprotein receptor
LFA1
lymphocyte function-associated antigen 1
LIGHT
homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes
M-CSF
macrophage-colony stimulating factor
MHC
major histocompatibility complex
MIF
macrophage migration inhibitory factor
miRNA
micro RNA
mmLDL
minimally modified LDL
MMP
matrix metalloproteinase
LXR
liver X receptors
NK
natural killer
NOD
nucleotide-binding oligomerization domain
NLR
NOD-like receptor
NLRP3
NLR family, pyrin domain containing 3
NPC
Niemann-Pick disease, type C
OxLDL
oxidized LDL
PAI
plasminogen activator inhibitor
PECAM-1
platelet endothelial cell adhesion molecule-1
PRR
pattern recognition receptor
RCT
reverse cholesterol transport
ROS
reactive oxygen species
SMCs
smooth muscle cells
SOCS
suppressor of cytokine signaling
SR
scavenger receptor
SREBP
sterol response element binding protein
SR-PSOX
SR that binds phosphatidyl serine and oxidized lipoprotein
STAT1
signal transducer and activator of transcription-1
TF
tissue factor
TGF
transforming growth factor
Th
T-helper
TIMP
tissue inhibitor of metalloproteinases
TNF
tumor necrosis factor
TL1A
TNF-like protein 1A
TNFSF12
TNF superfamily member 12
TLR
Toll-like receptor
TRAIL
TNF-related apoptosis-inducing ligand
Tregs
regulatory T cells
TWEAK
TNF-related weak inducer of apoptosis
VCAM-1
vascular cell adhesion molecule-1
VLA4
very late antigen 4
wt
wild type

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Dipak Ramji received his BSc (Hons) degree (Biochemistry) and his PhD from University of Leeds. This was followed by post-doctoral research at the EMBL (Heidelberg) and IRBM (Rome) with fellowships from the Royal Society and the EU. He joined Cardiff University in 1992 and is currently a Reader at Cardiff School of Biosciences. His research is focused on the impact of the immune and inflammatory responses in atherosclerosis with emphasis on the action of cytokines on macrophages. He has published over 70 peer-reviewed papers, reviews and book chapters.

Thomas Davies received his BSc (Hons) degree (Genetics) from Cardiff University in 2009, completing his PhD, also at Cardiff University, in 2013. His PhD project was focused on the characterization of Ca2+-signaling mechanisms in vascular tone and vascular calcification in the arterial-expressed extracellular calcium-sensing receptor. His current post-doctoral research aims to delineate the roles of the JAK/STAT and ERK1/2 axis in interferon-gamma-mediated signaling in macrophage-dependent atherosclerotic plaque development.