Atherosclerosis, or hardening of the arteries,
develops when plaque — particularly cholesterol,
fatty substances, cellular debris and calcium
deposits — accumulates on artery walls. It is widely
accepted that atherosclerosis develops as a chronic
inflammatory process.
Cholesterol that accumulates in the blood vessel
walls results in the precipitation of cholesterol
crystals, previously thought to be inert, but
cholesterol crystals (CC) induce inflammation that
is critical in the initiation and progression of
atherosclerosis.
Researchers at the Center of Molecular Inflammation
Research (CEMIR) recently published new data on how
high density lipoprotein (good cholesterol HDL)
attenuates inflammatory responses initiated by
cholesterol crystals (CC). These data could be of
significant interest for management of
atherosclerosis.
Traditionally, HDL has been perceived as beneficial
because it carries away cholesterol from the artery
walls. It also has several other good qualities:
among other things, it is an antioxidant, and it
protects blood vessels’ surface cells. So it turns
out that the good cholesterol, or at least an
artificial variant of it, helps to slow the
inflammatory process caused by cholesterol crystals.
As Nathalie Niyonzima explains (Niyonzima is a
researcher at CEMIR, the Centre of Molecular
Inflammation Research at NTNU) the immune system
identifies the cholesterol crystals as harmful
substances in the body that need to be removed. But
the antibodies that come to the body’s defence are
unable to break down the crystals. The immune system
calls out for reinforcements, and more antibodies
arrive, to no avail. The immune reaction runs wild,
and the inflammation process escalates.
Once believed as a disease of cholesterol storage,
atherosclerosis is now acknowledged as an
inflammatory disease that is shaped by cells and
signalling molecules from the innate and the
adaptive immune systems in various ways.
Researchers have shown that cholesterol which
accumulates in atherosclerotic lesions in the form
of cholesterol esters in foam cells or as
crystalline cholesterol, can initiate the
development and progression of atherosclerosis.
The chronic inflammation initiated by cholesterol
crystals is a result of the inability of cells to
degrade these crystals.
Researchers at CEMIR have previously published that
there is a link between the complement system and
NLRP3 inflammasome activation by cholesterol
crystals (CC). The complement system is a part of
the innate immune system that controls several
aspects of CC-induced inflammation such as
phagocytosis and release of pro-inflammatory
cytokines.
To test the effect of cholesterol crystals,
researchers used blood samples from healthy
volunteer donors – many of whom were colleagues in
the same department.
In healthy blood samples all the natural components
are present, allowing us to study all the
mechanisms. When we added cholesterol crystals, we
saw that the complement system—an important part of
the innate immune system—was activated. Adding the
cholesterol crystals triggered an immune reaction
that eventually got out of control, resulting in
inflammation. Researchers at CEMIR were the first to
show that cholesterol crystals can trigger
inflammation by activating the complement system.
Now other studies have confirmed this result.
Scientists found that CC lose their
immunostimulatory potential once exposed to rHDL.
Exploring the anti-inflammatory mechanisms of rHDL
on CC-induced inflammation, researchers found that
rHDL bound strongly to CC, and that this interaction
resulted in reduced deposition of activated
complement products on CC and a drop in complement
activation. As a consequence of complement
inhibition, the pro-inflammatory cytokine release in
whole blood was significantly reduced.
This study demonstrates a new anti-inflammatory
mechanism whereby rHDL inhibits complement
activation by CC. These data may be of significance
in controlling the progression of atherosclerosis.
For more information
Niyonzima, N. et al. Reconstituted High-Density
Lipoprotein Attenuates Cholesterol Crystal-Induced
Inflammatory Responses by Reducing Complement
Activation. Journal of immunology 195, 257–264
(2015)
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