As Macrophages Fill With Oxidized Cholesterol, They Become Foam Cells:
Further investigating the differences of macrophages regulating ECM to promote cardiac regeneration or cardiac fibrosis will help provide new therapeutic ideas for cardiac regeneration therapy. This over here figure shows the origin of infiltrating monocytes in the bone marrow after tissue injury. Ly6Chi macrophages can mature and differentiate into Ly6Clo macrophages after infiltrating tissues.
During atherogenesis, cholesterol efflux is impaired by the combined effect of dampened lipolysis, lysosomal dysfunction caused by free cholesterol accumulation, altered cholesterol trafficking, impaired lipophagy, and downregulated reverse cholesterol transport [51, 89’93]. The notion that foam cells contribute to maladaptive responses derives from findings that foam cells tend to lose immune functions, induce tissue damage, and sustain survival of intracellular pathogens (Figure 1) [7’10]. PL is also the most abundant lipid category and the main component of the plasma membrane (PM) and membranes of the intracellular organelles [29,52,53]. Hi-oxLDL-induced foam cells contained 4 times more total PL than untreated control cells (Figure 5C top).
Tsai et al. found that after knocking down CXCL8 with morphine during the limb regeneration of axolotl, the regeneration rate of the limb was significantly reduced. At the same time, Tsai et al. found that after the undamaged limbs overexpressed IL-8, the recruitment of macrophages increased significantly. This research proved that CXCL8 plays an early immunomodulatory role during the limb regeneration of the axolotl, and through coupling with its homologous receptor CXCR-1/2, CXCL8 signaling is necessary for limb regeneration (de Oliveira et al., 2013). Because CD146 expression on foam cells is involved in oxLDL-induced activation, we then evaluated the possible involvement of CD146 in the uptake of oxLDL by macrophages. Oil red O staining showed that blocking of CD146 with AA98 or with genetic knockdown in macrophages impaired oxLDL uptake (Figure 3A), indicating that CD146 contributes to the uptake of oxLDL by macrophages.
Exploring the relevant mechanisms involved in the process of peripheral nerve regeneration will help to develop new regenerative therapies for nerve injury. After bestowing transverse damage to the peripheral nerve, the distal axon is separated from the cell body. Subsequently, the myelin ovum disintegrates to produce a large number of myelin fragments, and the expression of regeneration-related genes in the neuron cell body try what he says is up-regulated to promote the regeneration of the proximal axon, and finally remyelination to complete the nerve regeneration (Fig. 4). During this process, delayed Waller degeneration and slow or insufficient removal of myelin necrotic fragments can inhibit axon regeneration (Stoll, Jander & Myers, 2002). In summary, different types of macrophages play an important role in the regeneration of the liver after injury.
Alternatively, LDL, when present at hyperlipidemic concentrations, can be engulfed by macrophages via pinocytosis [144] and lipolytic enzymes present in the intima can also generate modified forms of LDL that are taken up by macrophages using scavenger receptor independent pathways [145]. Under normal conditions, lipids taken up by macrophages are typically processed and effluxed from the cells preventing the generation of foam cells (described above). However, as there appears to be little negative feedback, during dyslipidaemia excessive lipid uptake by macrophages results in defective cholesterol trafficking and lipid efflux and the generation of foam cells engorged with lipid [28], affecting macrophage phenotype and compromising immune functions. A potential limitation of the present work is that it focused on the mRNA expression of selected genes, which does not always reflect the standard dichotomy of the translational process into a functional protein. Nevertheless, our study demonstrates distinct metabolic responses to cellular cholesterol loading and cholesterol efflux in M-CSF- and GM-CSF-differentiated human macrophages in vitro. Importantly, the effects of cholesterol loading on the studied genes were segregated into those remaining as quiescent markers of the CSF-polarized cells, e.g. the CD antigens, and those altering their expression in the foam cells, notably ABCG1 and CCL2.
We evaluated macrophage survival in response to free cholesterol loading as an atherosclerosis-relevant in vitro model of macrophage death12. Trem2-/- BMDMs showed reduced survival upon free cholesterol loading (Fig. 3d’e), whereas the opposite was seen in 4D9-treated BMDMs (Fig. 3f), indicating that TREM2 promotes macrophage foam cell survival. Mitochondrial potential in remaining viable macrophages was reduced in Trem2-/- BMDMs and increased in 4D9-treated BMDMs (Fig. 3g), consistent with previous work linking TREM2 to phagocyte metabolic fitness during stress13. Taken together, it is clear that the presence or absence of lipids can have dramatic effects on macrophage biology, affecting their gene expression profile and ultimately their functions.
Now, new systems of drug supply (such as NPs, stents, liposomes, glucon shell microparticles, oligopeptide complexes, and monoclonal antibodies) allow the selective modification of macrophages. Macrophage surface markers (F4/80, CD11b, CD68, CD 206) and scavenger receptors enforce distinctive targets for all macrophages or different subsets [72]. In combination with surface coating receptors or depending on their chemical navigate here properties, these systems are able to provide drugs or RNA interference (RNAi) to local atherosclerotic plaques or specific subsets of macrophages, making changes with minimal nontargeted effects and toxicity [73]. Targeting macrophages, various approaches are able to be used to modulate their activity, including impelling cell apoptosis, cell proliferation suppression, and administering anti-inflammatory drugs.
Both doses of apoA-I (10 and 50 ‘g/mL) decreased total sterols, cholesterol, and oxysterols (Figure 3B). However, a statistically significant reduction was only accomplished by 50 ‘g/mL of apoA-I (Figure 3B). Interestingly, HDL treatment exerted a trend toward reduced total sterols, cholesterol, and oxysterols, but the degree of reduction was not significant possibly due to large variation among the samples in the group. Since cholesterol is enriched in LDL particles and human atherosclerotic plaques, many studies have been performed on cholesterol metabolism in atherosclerosis.
However, over time, more and more new data on the heterogeneity of foam cells appear, which will allow more efficient targeting options for atherosclerosis treatment. Within the framework of plaques, macrophages belonging to traditionally included and alternatively activated subsets participate in both human and mouse lesions. In human lesions, macrophages expressing proinflammatory markers are located in unstable areas predisposed to break, and M2-like macrophages are located in persistent areas and adventitia. However, recent data demonstrate that macrophages exist in the activation continuum, and that the M1/M2 classification system is a very strong simplification of the heterogeneity of macrophages and their various functions [49].
In the ischemia-reperfusion acute kidney injury model, the expression of M1-specific inflammatory factors (mainly IL-1 ‘, TNF-a, IL-12, IL-18, and IL-23) increased within 24 h after injury, and significantly decreased after three days (Lee et al., 2011). The activation of recruited macrophages begins to secrete these pro-inflammatory cytokines, which can lead to sustained enhancement of the inflammatory response at the injury site and acquisition of other inflammatory cells, such as Th cells. If M1 macrophages remain in their original shape after pathogenic or damaged cells are removed, their prolonged activation can lead to an excessive inflammatory response at the site of injury. Since the released cytotoxic molecules cannot distinguish between pathogens and normal cells, the cytotoxins will be detrimental to inflammatory absorption and damage repair. Excessive inflammatory response is also the main cause of many autoimmune kidneys damage (Kroner et al., 2014; Huen et al., 2015).
Recent studies revealed that the upregulation of neuroimmune guidance cues, netrin-1 or semaphorin 3E, under hypoxic conditions exacerbates plaque inflammation by promoting macrophage retention17,18,19. Therefore, inhibiting the formation of foam cells or restoring their capacity for emigration should facilitate resolution of chronic inflammation and improve clinical outcomes among patients with atherosclerosis4,6. Thus, identification of the underlying mechanisms that control foam cell formation and retention within the plaque may lead to the discovery of novel therapeutic targets in atherosclerosis2.