Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation

TY - JOUR

T1 - Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation

AU - Bakke, Siril S

AU - Aune, Marie H

AU - Niyonzima, Nathalie

AU - Pilely, Katrine

AU - Ryan, Liv

AU - Skjelland, Mona

AU - Garred, Peter

AU - Aukrust, Pål

AU - Halvorsen, Bente

AU - Latz, Eicke

AU - Damås, Jan K

AU - Mollnes, Tom E

AU - Espevik, Terje

N1 - Copyright © 2017 by The American Association of Immunologists, Inc.

PY - 2017/10/15

Y1 - 2017/10/15

N2 - Cholesterol crystals (CC) are abundant in atherosclerotic plaques and promote inflammatory responses via the complement system and inflammasome activation. Cyclic oligosaccharide 2-hydroxypropyl-b-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances. Recently we have shown that BCD has an anti-inflammatory effect on CC via suppression of the inflammasome and liver X receptor activation. The putative effects of BCD on CC-induced complement activation remain unknown. In this study, we found that BCD bound to CC and reduced deposition of Igs, pattern recognition molecules, and complement factors on CC in human plasma. Furthermore, BCD decreased complement activation as measured by terminal complement complex and lowered the expression of complement receptors on monocytes in whole blood in response to CC exposure. In line with this, BCD also reduced reactive oxygen species formation caused by CC in whole blood. Furthermore, BCD attenuated the CC-induced proinflammatory cytokine responses (e.g., IL-1a, MIP-1a, TNF, IL-6, and IL-8) as well as regulated a range of CC-induced genes in human PBMC. BCD also regulated complement-related genes in human carotid plaques treated ex vivo. Formation of terminal complement complex on other complement-activating structures such as monosodium urate crystals and zymosan was not affected by BCD. These data demonstrate that BCD inhibits CC-induced inflammatory responses, which may be explained by BCDmediated attenuation of complement activation. Thus, these findings support the potential for using BCD in treatment of atherosclerosis.

AB - Cholesterol crystals (CC) are abundant in atherosclerotic plaques and promote inflammatory responses via the complement system and inflammasome activation. Cyclic oligosaccharide 2-hydroxypropyl-b-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances. Recently we have shown that BCD has an anti-inflammatory effect on CC via suppression of the inflammasome and liver X receptor activation. The putative effects of BCD on CC-induced complement activation remain unknown. In this study, we found that BCD bound to CC and reduced deposition of Igs, pattern recognition molecules, and complement factors on CC in human plasma. Furthermore, BCD decreased complement activation as measured by terminal complement complex and lowered the expression of complement receptors on monocytes in whole blood in response to CC exposure. In line with this, BCD also reduced reactive oxygen species formation caused by CC in whole blood. Furthermore, BCD attenuated the CC-induced proinflammatory cytokine responses (e.g., IL-1a, MIP-1a, TNF, IL-6, and IL-8) as well as regulated a range of CC-induced genes in human PBMC. BCD also regulated complement-related genes in human carotid plaques treated ex vivo. Formation of terminal complement complex on other complement-activating structures such as monosodium urate crystals and zymosan was not affected by BCD. These data demonstrate that BCD inhibits CC-induced inflammatory responses, which may be explained by BCDmediated attenuation of complement activation. Thus, these findings support the potential for using BCD in treatment of atherosclerosis.

KW - Carotid Arteries

KW - Cells, Cultured

KW - Cholesterol

KW - Complement Activation

KW - Complement System Proteins

KW - Cyclodextrins

KW - Cytokines

KW - Humans

KW - Immunomodulation

KW - Inflammation

KW - Inflammation Mediators

KW - Leukocytes, Mononuclear

KW - Monocytes

KW - Plaque, Atherosclerotic

KW - Reactive Oxygen Species

KW - Journal Article

U2 - 10.4049/jimmunol.1700302

DO - 10.4049/jimmunol.1700302

M3 - Journal article

C2 - 28855312

SN - 0022-1767

VL - 199

SP - 2910

EP - 2920

JO - Journal of Immunology

JF - Journal of Immunology

IS - 8

ER -