Atherosclerosis is a condition of dysfunctional macrophages. Macrophages are responsible for clearing out lipids that end up in blood vessel walls, ingesting these misplaced lipid molecules and handing them off to HDL particles to be carried to the liver for excretion. This works just fine in youth, in an environment of low oxidative stress and few oxidized lipids. Aging brings chronic inflammation, oxidative stress, and oxidized lipids, however. Macrophages cannot process oxidized lipids all that well, and so become pathological, turning into inflammatory foam cells packed with lipids, and unable to do more than send signals for help. The plaques that form to narrow and weaken blood vessels in atherosclerosis might start out as lipid deposits, but become macrophage graveyards as they grow, as ever more macrophages arrive to try and fail to clear the damage.
A number of new approaches to atherosclerosis based on interfering in this process are under development. My company, Repair Biotechnologies, works on a way to allow macrophages to break down oxidized cholesterol in situ. Underdog Pharmaceuticals works on sequestration of the worst oxidized lipid, 7-ketocholesterol. And so forth. The work here, in which researchers identify the gene TRIB1 as a regulator of macrophage uptake of oxidized lipids, offers a new avenue of attack. The evidence presented is fairly compelling for some form of inhibition of TRIB1 to be the basis for a therapy. If this could be done for an extended period of time, then in principle atherosclerosis could be reversed, as macrophages become able to go about their duties and meaningfully clean up atherosclerotic lesions.
Research has shown for the first time that a protein expressed in a subset of immune cells contributes towards the build-up of fatty deposits in arteries, which leads to cardiovascular disease. These fatty deposits are caused by macrophages, a subset of immune cells known to take up surplus cholesterol. When this is present in excess, they mature into larger cholesterol-laden cells known as foam cells which accumulate and cause blockages inside arteries. The study shows for the first time that levels of a protein called Tribbles-1 (TRIB1) inside macrophages controls the amount of oxidized cholesterol taken up by foam cells. The research shows that higher levels of TRIB1 increased specific cholesterol uptake receptors, promoting arterial disease, whereas decreasing TRIB1 reduced disease. The findings of this study suggest that inhibiting TRIB1 in macrophages could be a viable therapeutic target in treating cardiovascular disease.
Atherosclerosis, a progressive disease of arterial blood vessels and the main underlying cause of stroke, myocardial infarction, and cardiac death, is initiated by the conversion of plaque macrophages to cholesterol-laden foam cells in the arterial intima. In the early-stage atherosclerotic plaque, this transformation is induced by the uptake of both low density lipoprotein-cholesterol (LDL-C) and oxidized LDL (oxLDL), which may serve a beneficial purpose; but unrestrained, the crucial function of plaque macrophages in resolving local inflammation is compromised, and the development of unstable, advanced lesions ensues.
Tribbles 1 (Trib1) has been detected in murine plaque-resident macrophages, and variants at the TRIB1 locus have been associated with increased risk of hyperlipidemia and atherosclerotic disease in multiple populations. However, no study had examined the macrophage-specific cellular processes dependent on myeloid-specific Trib1 expression and how these tally with the assumed atheroprotective properties of this pseudokinase. At the whole-body level, one study has shown that Trib1-deficient mice have markedly reduced numbers of M2-like macrophages in multiple organs, including adipose tissue. Hence, these studies strongly implicated that loss of macrophage-Trib1 expression within the arterial wall would lead to excessive atherosclerotic plaque inflammation and/or impair inflammation resolution and promote atheroma formation.
In the current study, we found that contrary to expectations, myeloid-specific knockout of Trib1 is atheroprotective, while myeloid-specific Trib1 expression is detrimental. In brief, Trib1 increased OLR1 RNA and protein expression, oxLDL uptake, foamy macrophage formation, and atherosclerotic burden in two distinct mouse models of human disease. The expression of these two genes, as well as those of LPL and SCARB1 (which mediates selective HDL-cholesterol uptake), is also tightly linked in human macrophages. Collectively, our studies reveal an unexpected beneficial effect for selectively silencing Trib1 in arterial plaque macrophages.