June 26, 2018

Targeting inflammation molecules reduces heart and liver disease in mice

At a Glance

  • Mice that produced an antibody against molecules thought to promote inflammation had reduced risk of diseases linked to a high-cholesterol diet.
  • Therapies targeting these molecules, called oxidized phospholipids, may also have promise in human disease prevention.
Mouse arteries The aorta (main artery) of a mouse on a high-fat diet for 12 months, top, has more plaques (bright red) than the aorta of the same type of mouse made to produce an antibody called E06, bottom. Que et al., Nature

The process of inflammation—a response of the immune system to danger—is vital to our health. It helps the body fight off microbes. It also jump-starts healing from cuts, scrapes, and other wounds. But too much inflammation can be harmful. Inflammation that persists over long periods of time may increase the risk of heart disease, cancer, and other health problems.

Past studies have shown that a class of molecules called oxidized phospholipids (OxPL) can trigger inflammation. Phospholipids are a major part of cell membranes. They are also found in the low-density lipoprotein (LDL) particles that carry cholesterol through the blood and contribute to some of the negative effects that long-term inflammation has on the body. OxPL are phospholipids that have been chemically modified (“oxidized”).

A team of researchers led by Drs. Xuchu Que and Joseph Witztum of the University of California, San Diego, have been investigating the potential role of OxPL in disease. In previous work, they created an antibody called E06 that can bind to OxPL. E06 prevents LDL with OxPL from being taken up by immune cells called macrophages. This is thought to be part of the process that leads to atherosclerosis, or hardening of the arteries, where plaques that build up in blood vessels can diminish blood flow.

In their new study, the team created a strain of mice that produces its own E06. They then tested whether the antibody altered the effects of a high-cholesterol diet. Their work was funded by several NIH components. Results were published online on June 6, 2018, in Nature.

As the researchers had hoped, the antibodies produced by the mice bound to OxPL-containing LDL. In lab experiments, it reduced the amount taken into macrophages by more than three-quarters. It also reduced the inflammation-promoting activity of those cells in the body.

Most significantly, mice that produced E06 had less atherosclerosis when fed a high-cholesterol diet than mice that didn’t produce the antibody. Atherosclerosis was reduced by 57% in the E06 mice at four months and 28% at 12 months. The antibody also reduced damage to heart valves, such as a narrowing of the valves (aortic stenosis).

In addition, mice that produced the antibody had less evidence of fatty liver disease (hepatic steatosis) while on the high-cholesterol diet. Overall, mice with E06 had 32% lower levels of a biomarker of systemic inflammation in their bodies than mice without the antibody. The mice that produced E06 also lived longer than those that didn’t.

These experiments are the first to show that OxPL directly contribute to inflammation and hardening of the arteries, Witztum explains. “This suggests that therapies that inactivate OxPL may be beneficial for reducing inflammation in general, and in particular in the case of diseases such as atherosclerosis, aortic stenosis, and hepatic steatosis,” he concludes.

—by Sharon Reynolds

Related Links

References: Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Que X, Hung MY, Yeang C, Gonen A, Prohaska TA, Sun X, Diehl C, Määttä A, Gaddis DE, Bowden K, Pattison J, MacDonald JG, Ylä-Herttuala S, Mellon PL, Hedrick CC, Ley K, Miller YI, Glass CK, Peterson KL, Binder CJ, Tsimikas S, Witztum JL. Nature. 2018 Jun 6. doi: 10.1038/s41586-018-0198-8. [Epub ahead of print]. PMID: 29875409.

Funding: NIH’s National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Environmental Health Sciences (NIEHS), and National Cancer Institute (NCI); Center for Human Nutrition; Leducq Foundation; and American Heart Association.