Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy |
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Authors: | McLaren James E Michael Daryn R Ashlin Tim G Ramji Dipak P |
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Affiliation: | Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom |
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Abstract: | Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-γ, transforming growth factor-β1, interleukin-1β, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis. |
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Keywords: | Abbreviations: ABCA-1/G-1, ATP-binding cassette transporter A-1/G-1 ACAT-1, Acyl-CoA:cholesterol acyltransferase-1 AcLDL, acetylated LDL ADRP, adipocyte differentiation related protein ApoE/A&ndash I, apolipoprotein E/A&ndash I BMMs, bone-marrow derived macrophages CD, cluster of differentiation CHOP, C/EBP-homologous protein CPT-1, carnitine palmitoyl transferase-1 CRP, C-reactive protein CXCL, chemokine (C&ndash X&ndash C motif) ligand CVD, cardiovascular disease DR3, Death Receptor 3 ECM, extracellular matrix FAs, non-esterified fatty acids HDL, high-density lipoprotein HL, hepatic lipase HMDMs, human monocyte-derived macrophages HMG CoA, 3-hydroxy-3-methylglutaryl-CoA ICAM1, intercellular adhesion molecule-1 IDL, intermediate density lipoprotein IFN, interferon IL, interleukin IMT, intima-media thickness JNK2, c-Jun N-terminal kinase 2 LIGHT, lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells LDL, low density lipoprotein LDLr, low density lipoprotein receptor LPL, lipoprotein lipase LXR, liver X receptor MAPK, mitogen activated protein kinase M1, classically activated macrophage M2, alternatively activated macrophage MCP-1, monocyte chemoattractant protein-1 M-CSF, macrophage-colony stimulating factor MMP, matrix metalloproteinase MPMs, murine peritoneal macrophages NPC, Niemann Pick type C NCEH, neutral cholesteryl ester hydrolase oxLDL, oxidized LDL PPAR, peroxisome proliferator-activated receptor sIFN-γR, soluble interferon-γ receptor SOCS3, suppressor of cytokine signaling 3 sPLA2, secretory phospholipase A2 SR, scavenger receptor SR-PSOX, scavenger receptor for phosphatidylserine and oxidized LDL Th, T-helper TGF-β1, transforming growth factor-β1 TL1A, TNF-like protein 1A TNF, tumor necrosis factor TNFR, tumor necrosis factor receptor TNFSF, tumor necrosis factor superfamily TWEAK, TNF-like weak inducer of apoptosis UPR, unfolded protein response VCAM-1, vascular cell adhesion molecule-1 VLDL, very low-density lipoprotein VSMC, vascular smooth muscle cell |
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