How cholesterol leads to clogged arteries

17 July 2015

The immunofluorescence micrograph  shows a cross section of a mouse atherosclerotic plaque where fragments of neutrophil extracellular traps (yellow overlay, stained for citrulinated histone 3 and myeloperoxidase) formed adjacent to the vascular endothelium (cell nuclei shown in blue) and the lipid (stained with the lipophilic dye Lipidtox).

Image: The immunofluorescence micrograph shows a cross section of a mouse atherosclerotic plaque where fragments of neutrophil extracellular traps (yellow overlay, stained for citrulinated histone 3 and myeloperoxidase) formed adjacent to the vascular endothelium (cell nuclei shown in blue) and the lipid (stained with the lipophilic dye Lipidtox). ©  Annika Warnatsch and Venizelos Papayannopoulos

A study by Francis Crick Institute researchers shows that when immune cells called neutrophils are exposed to cholesterol crystals, they release large extracellular web-like structures that trigger the production of inflammatory molecules linked to artherosclerosis.

Termed neutrophil extracellular traps (NETs), these web-like structures are primarily released to capture and kill certain pathogenic microorganisms. However, the authors now show that NETs also form in atherosclerotic lesions and lead to the production proinflammatory cytokines  and the accumulation of pathogenic immune cells in the lesion.

The findings shed light on the processes that promote artherosclerosis, a disease in which plaque builds up inside a patient's arteries. Atherosclerosis is among the most widespread of chronic inflammatory diseases and is a major cause of death in Western countries.

Dr Veni Papayannopoulos of the Crick (currently based at Mill Hill) explained: "Like many chronic inflammatory diseases, atherosclerosis is driven by molecules called proinflammatory cytokines. In atherosclerosis, these proteins orchestrate the continuous recruitment of immune cells to the arterial walls, leading to the build up of cholesterol-containing lesions that can obstruct blood flow."

"One of the key challenges in understanding inflammatory diseases that are not caused by infections is to discover what triggers the production of these inflammatory cytokines."

Previous work had showed that when the concentration of certain lipids increases in our blood, cholesterol crystals are produced. These crystals activate a process in immune cells called macrophages that is required to process proinflammatory cytokines into their mature and active form. However, it remained unclear how these molecules are produced in the first place.

The team used a variety of methods to shed light on the topic. First, they isolated human neutrophils from healthy individuals and showed that cholesterol crystals,  trigger neutrophils to release NETs.

They then placed mice on a high fat western diet to promote artherosclerosis and isolated their aortas (the main artery in their hearts) to measure the size of the artherosclerotic plaques and to look for the presence of NETs. Lastly, the team measured the concentrations of proinflammatory cytokines and inflammatory immune cells in these plaques and in the blood of the mice.

The research showed that exposure of neutrophils to cholesterol crystals promotes the release of NETs, which activate macrophages to produce proinflammatory cytokines and recruit additional disease-causing immune cells to the lesion.

However, mice with a genetic mutation that hampered the ability to release NETs in response to cholesterol crystals, and mice receiving treatments that degrade NETs, had substantially lower concentrations of proinflammatory cytokines and smaller lesions covering their aortas.

Dr Annika Warnatsch of the Crick (also at Mill Hill) said: "These findings explain how cholesterol crystals and other internal signals are sufficient to promote inflammation in the absence of infection.

"Our work sheds light on the mechanisms that drive atherosclerosis and potentially and other chronic inflammatory diseases and suggests new strategies for their treatment."

The paper, Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis, is published in Science.

  • New research from the  Francis Crick Institute shows the cellular processes that occur when cholesterol triggers inflammation linked to artherosclerosis.
  • Artherosclerosis is the build-up of fatty material inside the arteries. It is very common, and over time can cause the arteries to narrow so much that it can be hard for blood to get through. It can result in heart attacks and strokes, as well as other health problems.
  • The work was primarily supported by the Medical Research Council.