Reconstituted High-Density Lipoprotein Attenuates Cholesterol Crystal-Induced Inflammatory Responses by Reducing Complement Activation.

Nathalie Niyonzima,Siril S Bakke,Tom E Mollnes,Anne Mari Rokstad,Jan K Damås,Terje Espevik,Eivind O Samstad,Samuel D Wright,Marie H Aune,Eicke Latz,Liv Ryan

doi:10.4049/jimmunol.1403044

Abstract

Chronic inflammation of the arterial wall is a key element in the development of atherosclerosis, and cholesterol crystals (CC) that accumulate in plaques are associated with initiation and progression of the disease. We recently revealed a link between the complement system and CC-induced inflammasome caspase-1 activation, showing that the complement system is a key trigger in CC-induced inflammation. HDL exhibits cardioprotective and anti-inflammatory properties thought to explain its inverse correlation to cardiovascular risk. In this study, we sought to determine the effect of reconstituted HDL (rHDL) on CC-induced inflammation in a human whole blood model. rHDL bound to CC and inhibited the CC-induced complement activation as measured by soluble terminal C5b-9 formation and C3c deposition on the CC surface. rHDL attenuated the amount of CC-induced complement receptor 3 (CD11b/CD18) expression on monocytes and granulocytes, as well as reactive oxygen species generation. Moreover, addition of CC to whole blood resulted in release of proinflammatory cytokines that were inhibited by rHDL. Our results support and extend the notion that CC are potent triggers of inflammation, and that rHDL may have a beneficial role in controlling the CC-induced inflammatory responses by inhibiting complement deposition on the crystals.

Highlights

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When whole blood was incubated with cholesterol crystals (CC) for 15 min, both monocytes and granulocytes displayed a rapid increase in complement receptor 3 (CR3) expression, which was significantly (p, 0.01 for 100 mg/ml reconstituted HDL (rHDL)) reduced by preincubation of CC with rHDL (Fig. 1B, 1C)
We report that rHDL composed of lipoprotein apolipoprotein A-I (apoA-I) with PC as the sole phospholipid binds to CC and impairs the ability of CC to activate complement, and attenuates the inflammatory responses induced by CC

Summary

Introduction

We sought to determine the effect of reconstituted HDL (rHDL) on CC-induced inflammation in a human whole blood model. RHDL bound to CC and inhibited the CC-induced complement activation as measured by soluble terminal C5b-9 formation and C3c deposition on the CC surface. Our results support and extend the notion that CC are potent triggers of inflammation, and that rHDL may have a beneficial role in controlling the CC-induced inflammatory responses by inhibiting complement deposition on the crystals.

Results

Conclusion