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.
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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.