Today, we will be looking at a new study that is attempting to treat atherosclerosis, one of the biggest age-related killers globally. As we age, our risk of developing atherosclerosis rises along with related conditions, such as hypertension.

We will be taking a look at new research that has reversed atherosclerosis in mice and is on the road to clinical trials in the future. Before we do that, let’s talk a little bit about how the disease develops and how macrophages work.

What is atherosclerosis?

Atherosclerosis is an age-related disease in which toxic, oxidized cholesterol deposits in the bloodstream cause inflammation in the arterial walls. This causes macrophages to swarm to the toxic cholesterol deposits, where they become either M1 inflammatory or M2 healing cell types, depending on the signals there.

Unfortunately, macrophages are not as robust as we might like, and, over time, they ingest so much waste that they either die outright or become senescent and turn into foam cells. Also, as we age, the immune system declines; again, this causes macrophages to increasingly become dysfunctional.







Foam cells are dysfunctional macrophages that increase inflammation and become embedded in the arterial walls. The rising inflammation then brings in more macrophages, which also succumb to the same fate over time.

This accumulation of dead and dying macrophages is the basis of the plaques that lead to atherosclerosis. They build up and eventually rupture, causing clots to break off, leading to heart attack and stroke.

The macrophages

The macrophages are immune cells derived from monocytes or leukocytes, which are types of white blood cells. They are involved in the housekeeping of the body and are responsible for clearing away debris and destroying harmful pathogens and damaged cells.

Recently, their role in regulating the healing and tissue repair process has been the focus of research.







The macrophages involved in tissue maintenance and repair appear to be divided into a number of different classes, each of which has its own functions, much like T-cells do. For this article, the two types of macrophages of interest to us are the M1 and M2 classes, and what type they are is known as polarization.

Both of these play an important role in regeneration; however, the M1 macrophages are less helpful, causing inflammation and fibrosis. M2 macrophages, on the other hand, are far more helpful: they suppress inflammation and encourage tissue growth by improving the cellular environment.

During an immune response, the M1 macrophages go in first and cause inflammation by secreting proinflammatory cytokines (signals) that attract other immune cells to the area to combat pathogens and dispose of waste.

The M2 types then follow up and act as “healing” macrophages to facilitate repair and regeneration of tissue after the battle.

Adjusting the ratios for tissue repair and cancer







Researchers have found that they can improve tissue regeneration by increasing the ratio of M2 to M1 macrophages and thus facilitate better tissue repair. The more M2 and the less M1 macrophages there are, the better the regrowth of tissues is.

Some researchers have also explored adjusting the ratio the other way, increasing the number of M1 macrophages in order to help destroy cancer. M1 macrophages are aggressive and cause more inflammation, which can help destroy cancer cells, although having too many of them bears the risk of excessive inflammation and fibrosis. So, any cancer therapy would have to take this into account.

New research reverses atherosclerosis

A team of researchers has shown how adjusting the ratio of M1 and M2 macrophages could be the basis for a treatment for heart disease in the results of a new study. By increasing the number of M2 macrophages, the researchers were able to not merely slow down the progression of atherosclerosis but to reverse it altogether.

The study authors confirmed that monocytes arriving at the site of plaques where atherosclerosis is regressing turn into M2 “healing” macrophages. The M2 macrophages promptly set about suppressing inflammation caused by the M1 macrophages during the initial immune response and prevent the plaque ruptures that cause clots.







The research team transplanted plaques from diseased mice into the arteries of healthy mice, and they observed dramatic drops in cholesterol levels. This drop has been shown to trigger monocytes to favor becoming M2 rather than M1 macrophages, thus helping plaque regression.

It is not currently known whether cholesterol lowering triggers this switch to M2 macrophages in humans, but new imaging techniques may soon allow researchers to detect changes to the ratio of M1 to M2 macrophages present in plaques.

Meanwhile, if researchers can work out how to boost the switch to M2 macrophages, a number of clinical approaches may become possible in time to benefit from these advances in imaging techniques.

Searching for the signal

The race is now on to develop therapies that can boost the ratio of M2 macrophages in cases where the disease has not yet reached the stage of clot formation, at which point it cannot be reversed by this approach. This therapy could be used in a preventative manner before the pathology develops to an untreatable point.







The team has identified the type of cell from which M2 macrophages arise, and they are now searching to identify the local signals that trigger them to change into M2s. Possible candidates are the immune signalling proteins interleukin-4 and interleukin-13, which past studies show are linked to the M2 transformation process.

These two interleukins are known to activate the STAT6 pathway, sending the protein to the cell nucleus, where it causes genes to be expressed that change it into an M2 macrophage. The researchers tested this hypothesis by inhibiting the action of STAT6, which resulted in a reduced number of M2 macrophages in regressing plaques.

The next step

The research team led by Dr. Fisher is already experimenting with nanoparticles based on the structure of “good cholesterol”, which is known to remove cholesterol waste from plaques and send it to the liver to be disposed of.

The team is currently testing a version of its nanoparticle that delivers interleukin 4 to plaques, and plans are in motion to move to a study in pigs. Should this study prove a success, the stage would be set for human clinical trials.







Conclusion

While the research is only in the preclinical stage, it is exciting nonetheless. If these results translate to pigs, they will pave the way for a preventative therapy against one of the biggest killers globally.

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Literature

[1] Karishma Rahman, Yuliya Vengrenyuk, Stephen A. Ramsey, Noemi Rotllan Vila, Natasha M. Girgis, Jianhua Liu, Viktoria Gusarova, Jesper Gromada, Ada Weinstock, Kathryn J. Moore, P’ng Loke, and Edward A. Fisher (2017). Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest. doi:10.1172/JCI75005.





