This research neatly demonstrates two quite different points. Firstly, that increased autophagy in our cells is generally a good thing, and a good basis for a range of therapies. It makes cells more efficient and more resistant to stress. Secondly, that finding ways to make the immune cells known as macrophages more efficient and more resistant to stress helps to slow the progression of atherosclerosis. Macrophages are responsible for cleaning up the oxidized lipids and fatty garbage that form the atherosclerotic plaques that disrupt blood vessel structure. Unfortunately these cells are easily overwhelmed, and much of the mass of these plaques in fact consists of the debris from dead macrophages by the time the disease reaches its dangerous later stages, in which major blood vessels are vulnerable to rupture. There are other studies to show that any method of making macrophages tougher and more resilient helps. That said, I think that the best class of approach to this challenge is to find ways to break down and remove at least the most challenging of the lipids, rather than trying to engineer a better class of macrophage. The former should be easier than the latter.
Studying mice, researchers have shown that a natural sugar called trehalose revs up the immune system's cellular housekeeping abilities. These souped-up housecleaners then are able to reduce atherosclerotic plaque that has built up inside arteries. Such plaques are a hallmark of cardiovascular disease and lead to an increased risk of heart attack. "We are interested in enhancing the ability of these immune cells, called macrophages, to degrade cellular garbage - making them super-macrophages."
Macrophages are immune cells responsible for cleaning up many types of cellular waste, including misshapen proteins and excess fat droplets. "In atherosclerosis, macrophages try to fix damage to the artery by cleaning up the area, but they get overwhelmed by the inflammatory nature of the plaques. Their housekeeping process gets gummed up. So their friends rush in to try to clean up the bigger mess and also become part of the problem. A soup starts building up - dying cells, more lipids. The plaque grows and grows."
The showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured in the aortic root were variable, but on average, the plaques measured 0.35 square millimeters in control mice compared with 0.25 square millimeters in the mice receiving trehalose, which translated into a roughly 30 percent decrease in plaque size. The difference was statistically significant, according to the study. The effect disappeared when the mice were given trehalose orally or when they were injected with other types of sugar, even those with similar structures.
Past work by many research groups has shown trehalose triggers an important cellular process called autophagy, or self-eating. But just how it boosts autophagy has been unknown. In this study, researchers show that trehalose operates by activating a molecule called TFEB. Activated TFEB goes into the nucleus of macrophages and binds to DNA. That binding turns on specific genes, setting off a chain of events that results in the assembly of additional housekeeping machinery - more of the organelles that function as garbage collectors and incinerators. "Trehalose is not just enhancing the housekeeping machinery that's already there. It's triggering the cell to make new machinery. This results in more autophagy - the cell starts a degradation fest. Is this the only way that trehalose works to enhance autophagy by macrophages? We can't say that for sure - we're still testing that. But is it a predominant process? Yes."