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. 2020 Jul 26;12(7):303–333. doi: 10.4330/wjc.v12.i7.303

Figure 1.

Figure 1

Macrophage phenotype in response to lipids and other factors within atherosclerotic lesions. Oxidized low density lipoprotein particles are composed of a number of components including (modified) apolipoprotein B, (oxidized) free cholesterol, (oxidized) cholesteryl esters and (oxidized) phospholipids, which induce a range of unique transcriptional responses in macrophages (indicated by arrows), resulting in altered expression of secreted cytokines and cell surface receptors, and differing macrophage phenotypes (highlighted in bold). Macrophages can be polarised to a pro-inflammatory phenotype by components of oxidized LDL in a number of differing ways. Cholesterol crystals activate the inflammasome to increase expression of interleukin-1 (IL-1), while cholesteryl ester hydroperoxides activate phospho-extracellular signal-regulated protein kinases 1 and 2 (pERK1/2) and phospho-protein kinase B (pAkt) pathways, resulting in induction of peroxisome proliferator activated receptor alpha and increased expression of C-X-C motif ligand 8 (CXCL8) and the scavenger receptor, cluster of differentiation 36 (CD36). The modified cholesterol metabolite, 7-ketocholesterol, also triggers pAkt and pERK1/2 signalling, resulting in activation of nuclear factor kappa B (NF-κB), and enhanced output of pro-inflammatory cytokines such as IL-6 and CXCL8; this oxysterol also increases expression of CD36 and CD68, potentiating uptake of modified lipoproteins, and represses expression of ATP binding cassette transporter A1 (ABCA1) and ABCG1, limiting cholesterol removal via apolipoprotein A-I (apoA-I) and high density lipoprotein. By contrast, other components of oxLDL can induce an anti-inflammatory phenotype: For example, 9-oxononanoyl cholesterol induces expression of transforming growth factor β and stimulates fibrosis. Short chain oxidized phospholipids interact with CD36 to activate cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1), while long chain oxidized phospholipids bind toll-like receptor-2, resulting in activation of nuclear factor erythroid-2-related factor 2 which enhances expression of antioxidant genes, including HO-1, to protect cells against further oxidative damage. Other factors found within atherosclerotic lesions can also influence macrophage phenotype: For example, the chemokine CXCL4 induces the expression of pro-inflammatory factors such IL-6, tumor necrosis factor α, matrix metalloproteinase 7 and S100 calcium binding protein A8, while repressing the expression of ABCG1, HO-1, CD36, scavenger receptor-A and CD163. Alternatively an anti-inflammatory and antioxidant phenotype can be induced by the interaction of hemoglobin:haptoglobin complexes with CD163, which activates phospho-activating transcription factor-1, resulting in changes in LXR expression, induction of HO-1 and increased expression of IL-10 and ABCA1. IL: Interleukin; TGF: Transforming growth factor; TNF: Tumor necrosis factor; HO-1: Heme oxygenase-1; MMP: Matrix metalloproteinase; LXR: Liver X receptor; ABCA1: ATP binding cassette transporter A1; HDL: High density lipoprotein; pAkt: Phospho-protein kinase B; NF-κB: Nuclear factor kappa B; pATF-1: Phospho-activating transcription factor-1; PPAR-α: Peroxisome proliferator activated receptor alpha; CXCL: C-X-C motif ligand; ABCG1: ATP binding cassette transporter G1.