Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation
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Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation. / Bakke, Siril S; Aune, Marie H; Niyonzima, Nathalie; Pilely, Katrine; Ryan, Liv; Skjelland, Mona; Garred, Peter; Aukrust, Pål; Halvorsen, Bente; Latz, Eicke; Damås, Jan K; Mollnes, Tom E; Espevik, Terje.
In: Journal of Immunology, Vol. 199, No. 8, 15.10.2017, p. 2910-2920.Research output: Contribution to journal › Journal article › Research › peer-review
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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-β-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-1α, MIP-1α, 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 BCD-mediated 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-β-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-1α, MIP-1α, 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 BCD-mediated 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
VL - 199
SP - 2910
EP - 2920
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 8
ER -
ID: 185404060