As Macrophages Fill With Oxidized Cholesterol, They Become Foam Cells:
Tuberculosis-infected human monocyte-derived macrophages shows that bacilli-containing phagosomes migrate toward the host cell lipid droplets and the bacilli are ultimately engulfed by the lipid droplets [7]. Tuberculosis can then acquire free fatty acids from host lipid droplet triglycerides and use them for biosynthesis of its triglyceride-rich lipid inclusions [61]. When mycobacteria accumulate lipid inclusions in lipid droplet-rich macrophages, they enter a dormancy state, change the composition of their cell wall, and become less great post to read readily killed by drugs [61]. Collectively, these findings suggest that intracellular pathogens might alter organelle trafficking in host cells to acquire lipids stored in host droplets and use them as an energy source for replication or survival. Hepatic macrophages can also eliminate apoptotic cells and reduce pro-inflammatory and pro-fibrotic signals depending on their phagocytosis. CX3CR1 has also been shown to inhibit and reverse liver fibrosis by controlling the differentiation and survival of monocyte-derived macrophages.
This is confirmed by the high expression of macrophage markers and the low content of smooth muscle cell markers. Further impact to signals inside the plaque (e.g., TGF-‘, oxidized lipids, and cytokines) are able to cause transdifferentiation of synthetic SMCs into foam cells. It is worth noting that cholesterol itself has been shown to trigger transdifferentiation of mouse SMCs and an elevation in the expression of CD68, Mac-2, and ABCA1 foam cell markers [67].
In atherosclerosis, monocytes are classified as classical and non-classical monocytes (14). Ly6Chigh monocytes in mice are categorized as classical monocytes, which are most comparable to the human CD14++/CD16′ subtype of monocytes. Ly6Clow cluster of monocytes in mice is classified as non-classical monocytes, which are comparable to the human CD14+/CD16++ cluster (~10%). The role of classical and non-classical monocytes in the progression of atherosclerosis is under debate. The classical or ‘proinflammatory’ monocytes enter into areas of endothelial injury (15, 16).
After washing, adherent macrophages were lyzed in RA1 lysis buffer (with added ‘-mercaptoethanol) from a NucleoSpin RNA Extraction Kit (Macherey-Nagel). Juan Li performed the experiments, prepared figures and/or tables, and approved the final the advantage draft. Written informed consent was obtained from each patient, and prior to sample collection, ethics approval was obtained from the Ethics Committee of the Anzhen Hospital and the Institute of Biophysics, Chinese Academy of Sciences.
Consistent with this result, the ApoE-/- mice that had been fed a Western diet for 18 weeks, displayed a similar staining pattern of CD146 and Mac-3 (a marker for murine macrophages) in their aortic plaques (Figure 1B). These data indicate that the expression of CD146 on macrophage foam cells is a common feature of mouse and human atheroma. Although the accumulation of macrophages in the artery wall has long been considered a major inducer of chronic inflammation, the mechanism that regulates formation of macrophage foam cells and their retention within the atheroma remains largely unknown4,7. Macrophages can emigrate at the early plaque stage9 or during atherosclerosis regression, but they become foam cells and gradually lose the capacity for emigration during progression of the atherosclerotic lesion6,7,10. There is growing evidence supporting the notion that the balance between retention and emigration signals contributes to the accumulation of macrophages in plaques. Researchers are only beginning to elucidate the regulatory signals that control macrophage emigration or retention6,7.
Targeting components of cholesterol uptake/esterification/efflux should be of great therapeutic value. Statins (lipid-lowering agents) were shown to possess a wide range of anti-inflammatory activities including improvement of lipid handling by macrophages in patients with cardiovascular disease. Simvastatin showed beneficial effects in the treatment of stroke-prone hypertensive rats via decreasing macrophage infiltration and lipid deposition and inhibition of LOX-1 expression 138. Similarly, pravastatin also reduced LOX-1 expression in intimal macrophages and decreased lipid core size in the atherosclerotic plaques of Watanabe heritable hyperlipidaemic rabbits 139.
Stimulation of these foam cells with apoA-I enhanced cholesterol efflux from hi-oxLDL-loaded foam cells like in acLDL-loaded foam cells (Figure 2A). HDL also enhanced cholesterol efflux from both acLDL- and hi-oxLDL-loaded foam cells (Figure S1). Intracellular free sterols, such as cholesterol and oxysterols, activate LXRs, resulting in increased expression of cholesterol transporters (e.g., ABCA1) to facilitate cholesterol efflux [45]. We also found that cells treated with hi-oxLDL had increased levels of ABCA1; conversely, treating cells with apoA-I or HDL decreased ABCA1, indicating possible clearance of intracellular free sterols (Figure 2B,C).
Apoptotic macrophages must be cleared by other macrophages in the vicinity by efferocytosis. In atherosclerosis, the dysregulated lipid metabolism in macrophages prevents effective efferocytosis and this coupled with the increase in macrophage apoptosis results in secondary necrosis [155], [156]. One mechanism for this is the cleavage of the efferocytosis receptor MerTK from macrophages by ADAM17 [157], [158], [159], [160], [161]. The subsequent release of intracellular components into the local environment contributes to the establishment of a necrotic core in the plaque. This is a feature of advanced atherosclerotic plaques and can contribute to plaque rupture.
However, in atherosclerosis, there is a deregulation of cholesterol uptake and reverse transport by macrophages. OxLDL, which is a major source of cholesterol, contributes to the suppression of cholesterol efflux, whereas expression of SRs especially LOX-1 becomes significantly up-regulated. Indeed, it is not surprising that the genetic deletion of either SR-A1 or CD36 has no beneficial effects in ApoE-deficient mice 38, 39 because oxLDL uptake by macrophages could be compensated by SR-BI (in early atherosclerosis) and LOX-1. The ACAT1 expression and activity are extensively modulated by different signalling messengers. Leptin, a hormone produced by adipose tissue, stimulates ACAT1 expression through Janus-activated kinase 2 (Jak2)/phosphatidylinositide 3-kinase (PI3K) mechanism 78. Insulin also up-regulates ACAT1 expression in macrophages via extracellular signal-regulated kinase (Erk)/p38MAP kinase/Jnk-dependent activation of CCAAT/enhancer binding protein a, a transcriptional regulator 79, 80.
One example is multiple sclerosis (MS), where myelin-laden foam cells are found in lesions of the central nervous system [3]. The levels of several TLR signaling molecules are regulated at the transcriptional level by noncoding RNAs, such as microRNA (miRNA). MiRNAs are small, approximately 20’24-nucleotide-long RNAs that generally bind to 3 untranslated regions of mRNAs. Studies have profiled miRNA expression in polarized macrophages to better understand their biological function. In general, miRNA profiling shows significant differences between human and mouse macrophages.
Pursuing their inflammatory phenotype, they express proinflammatory transcription factors as nuclear factor-kB and STAT (signal transformer and transcription activator)-1. M2 macrophages exist at the other spectrums’ end with a phenotype hinged on the oxidation of the fatty acids, and anti-inflammatory properties [46]. M2 macrophages are polarized in response to the cytokines IL-4 and IL-13 and secrete anti-inflammatory factors including collagen and IL-1 receptor more info agonist, IL-10. M2 macrophages are characterized by the expression of CD163 (cluster of differentiation 163), mannose receptor 1, resistin-like ‘, and an increased level of arginase-1 [47]. Tuberculosis-infected macrophages can also result from impaired host lipolysis by a mechanism in which 3-hydroxybutyrate (3HB), secreted by macrophages, binds G protein-coupled receptor GPCR109A, which modulates the cAMP-dependent signaling pathway in THP-1 cells [70].
Atherosclerosis is a major underlying cause of cardiovascular diseases including stroke, coronary artery disease, and peripheral artery disease. Now widely understood as a chronic inflammatory disease, atherosclerosis develops due to progressive accumulation of cholesterol-rich low-density lipoproteins (LDL) and immune cells within the arterial wall that eventually form lipid-rich plaques [1]. The arterial wall undergoes extensive remodeling of the extracellular matrix (ECM) resulting in the characteristic global increase in arterial stiffness and focal regions of decreased stiffness [2’4]. As discussed, the formation of foam cells leads to the progression of fatty streaks that eventually turn into very developed plaques. Because of this, atherosclerosis often develops into diseases, such as coronary heart disease and strokes. M2 macrophages have increased IL-10 and suppressed IL-12 secretion, which reduces excessive inflammation and facilitates collagen production and fibrosis, which aids with healing.
Free cholesterol could be removed from macrophages through active transfer mediated by cholesterol transporters or by passive transmembrane diffusion. Cholesterol transporters such as ABCA1, ABCG1 and SR-Bi play the major role in active free cholesterol efflux. The purpose of this review is to characterize key mechanisms of cholesterol efflux, specifically in macrophages. In this work we briefly consider all constituents of the system responsible for cholesterol metabolism in macrophages.