Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy

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. 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–I, apolipoprotein E/A–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–X–C motif) ligand; CVD, cardiovasculardisease; 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