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New anti-inflammatory effects of the HDL good cholesterol (2015-11-12)

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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