Macrophages in Athersclerosis Flashcards
What is the primary role of macrophages, and how do they do this?
The identification and degradation of pathogens, cell debris and cancer cells – endocytosing them via pattern recognition receptors and engulfing them in a phagosome, which then merges with the lysosome to degrade the pathogen before exocytosing the remnant material and displaying the antigens.
The activity of this process triggers the release of pro-inflammatory cytokines.
How are macrophages attracted to the endothelium?
Monocytes are attracted to the endothelium by chemokine attractants such as CCL5 and CXCL1, which are released due to the inflammation caused by LDL accumulation and subsequent endothelial activation.
How are macrophages recruited into the endothelium?
The monocytes are recruited via diapedesis by the monocyte P-selectin glycoprotein ligand 1 (PGSL-1) when rolling and their firm adhesion is facilitated by binding the VLA-4 and LFA-1 integrins which dimerise with VCAM and ICAM respectively to mediate internalisation (E-selectin also being involved in these processes).
How does platelet recruitment to the endothelium in atherosclerosis affect macrophage recruitment?
It promotes monocyte-endothelium interactions through deposition of platelet-derived chemokines and its activation of NF-κB signalling, leading to increased expression of VCAM and ICAM.
How does CVD affect the immune cells?
Monocytes can in fact be modified prior to their recruitment by the high levels of plasma cholesterol characteristic of CVD.
How does high cholesterol affect monocytes?
During the production of monocytes from their bone-marrow derived progenitors (HSPCs – haematopoeitic stem/progenitor cells) the cholesterol begins to induce their later phenotype and also increase the numbers of monocytes in circulation.
This is mediated by cholesterol increasing the IL-3 concentration and stimulating the GM-CSF (granulocyte macrophage – CSF) receptor, both of which stimulate proliferation of the monocytes. In ApoE -/- mice monocyte levels are 50% higher than in wildtype.
What happens when monocytes are first internalised into the endothelium?
Once internalised these differentiate into macrophages due to monocyte colony stimulating factor (M-CSF) signalling and proliferate within the plaque.
What is the intended function of the macrophage within the fatty streak?
In the early stages these macrophages serve their intended purpose – clearing the apoptotic cells and LDLs from the lesion or fatty streak.
The LDLs taken up at this stage, even those taken up by scavenger receptors such as SR-A or CD36, are hydrolysed in endosomes and the cholesterol trafficked to the ER via the NPC1/2 pathway.
What effect does the OD of LDL have on the macrophages in the lesion?
Much of this free cholesterol is effluxed via ABCG1, but the large excess leads to esterification by ACAT and storage within the cell to produce foam cells.
Upregulating cholesterol efflux in macrophages is thus a major therapeutic target, as this is the primary mechanism of plaque regression.
What dysregulation occurs in foam cells due to the high lipid content?
The oxysterols and modified PLs from atherogenic lipoprotein uptake (ApoB-LPs) can lead to macrophage apoptosis, or in lesser conditions can enrich the plasma membrane with free cholesterol which activates inflammatory signalling receptors leading to increased cytokine production.
How do foam cells progress the lesion?
This is sufficiently worsened by their uncontrollable oxLDLs uptake (cholesterol loading) to produce enough foam cells to form a lipid lesion core.
New macrophages are still active at this point, but then promote progression of the lesion through degradation of the fibrous cap and thrombotic core formation.
What are cholesterol crystals?
A hallmark of advanced atherosclerosis that forms within lipid cores and is highly pro-inflammatory.
Macrophages attempt to engulf the cholesterol crystals, but this just makes everything worse.
How do cholesterol crystals affect macrophages?
During engulfing they cause endosome damage and subsequent lysosomal disruption, which in conjunction with the subsequent impairment of cathepsin B and L and hence the sterol response network, prevents proper cholesterol management and is hence highly pro-atherogenic.
Also by activating the macrophage inflammasome complex composed of NLRP3, ASC and caspase-1. This leads to increased IL-1β and IL-18 secretion, which act as chemokines to attract more monocytes.
What factors promote foam cell apoptosis in the lesion core?
Prolonged ER stress in the overloaded foam cells, as well as the often hypoxic conditions, lack of growth factors and activation of death receptors (IFN and TLR3/4 signalling), triggers apoptosis of the foam cells.
What factors prevent foam cell apoptosis in the lesion core?
In some cells this is prevented by the ER stress activating cell survival pathways including NF-κB, Akt, p38 kinases and autophagy, thus reducing necrotic core formation. This is, however, inhibited by the uptake of LDLs via scavenger receptors.
How does macrophage/foam cell apoptosis impact formation of the necrotic core and lesion progression?
Macrophage apoptosis itself does not cause necrosis, but defective clearance of the products by the remaining macrophages leads to secondary necrosis and formation of the necrotic core.
Macrophage cell death in early lesions can actually be beneficial, decreasing the inflammation and number of foam cells.
