Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment

Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly consid...

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Main Authors: Tom Houben, Tulasi Yadati, Robbin de Kruijf, Marion J. J. Gijbels, Joost J. F. P. Luiken, Marc van Zandvoort, Dimitris Kapsokalyvas, Dieter Lütjohann, Marit Westerterp, Jogchum Plat, David Leake, Ronit Shiri-Sverdlov
Format: Article
Language:English
Published: Frontiers Media S.A. 2021-08-01
Series:Frontiers in Immunology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2021.716357/full
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author Tom Houben
Tulasi Yadati
Robbin de Kruijf
Marion J. J. Gijbels
Joost J. F. P. Luiken
Marc van Zandvoort
Marc van Zandvoort
Marc van Zandvoort
Dimitris Kapsokalyvas
Dimitris Kapsokalyvas
Dimitris Kapsokalyvas
Dieter Lütjohann
Marit Westerterp
Jogchum Plat
David Leake
Ronit Shiri-Sverdlov
spellingShingle Tom Houben
Tulasi Yadati
Robbin de Kruijf
Marion J. J. Gijbels
Joost J. F. P. Luiken
Marc van Zandvoort
Marc van Zandvoort
Marc van Zandvoort
Dimitris Kapsokalyvas
Dimitris Kapsokalyvas
Dimitris Kapsokalyvas
Dieter Lütjohann
Marit Westerterp
Jogchum Plat
David Leake
Ronit Shiri-Sverdlov
Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment
Frontiers in Immunology
2-hydroxypropyl-β-cyclodextrin
metabolic inflammation
cholesterol
hepatic inflammation
macrophage
author_facet Tom Houben
Tulasi Yadati
Robbin de Kruijf
Marion J. J. Gijbels
Joost J. F. P. Luiken
Marc van Zandvoort
Marc van Zandvoort
Marc van Zandvoort
Dimitris Kapsokalyvas
Dimitris Kapsokalyvas
Dimitris Kapsokalyvas
Dieter Lütjohann
Marit Westerterp
Jogchum Plat
David Leake
Ronit Shiri-Sverdlov
author_sort Tom Houben
title Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment
title_short Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment
title_full Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment
title_fullStr Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment
title_full_unstemmed Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment
title_sort pro-inflammatory implications of 2-hydroxypropyl-β-cyclodextrin treatment
publisher Frontiers Media S.A.
series Frontiers in Immunology
issn 1664-3224
publishDate 2021-08-01
description Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound. Given its potential as a therapeutic compound in metabolic inflammatory diseases, in this study, we evaluated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (Ldlr-/) mice that were transplanted with Npc1nih or Npc1wt bone marrow and were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks, thereby creating an extreme model of lysosomal cholesterol-induced metabolic inflammation. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, the inflammatory properties of CD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While CD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after CD treatment, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in vitro in murine BMDMs and macrophages cell lines. Nevertheless, this CD-induced pro-inflammatory profile was time-dependent, as short term exposure to CD did not result in a pro-inflammatory response in BMDM. While CD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using CD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.
topic 2-hydroxypropyl-β-cyclodextrin
metabolic inflammation
cholesterol
hepatic inflammation
macrophage
url https://www.frontiersin.org/articles/10.3389/fimmu.2021.716357/full
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spelling doaj-bbd2929920734dc38c17c39f7b1179382021-08-20T13:49:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.716357716357Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin TreatmentTom Houben0Tulasi Yadati1Robbin de Kruijf2Marion J. J. Gijbels3Joost J. F. P. Luiken4Marc van Zandvoort5Marc van Zandvoort6Marc van Zandvoort7Dimitris Kapsokalyvas8Dimitris Kapsokalyvas9Dimitris Kapsokalyvas10Dieter Lütjohann11Marit Westerterp12Jogchum Plat13David Leake14Ronit Shiri-Sverdlov15Departments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsDepartments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsDepartments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsDepartments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsDepartments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsDepartments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsSchool for Oncology and Developmental Biology GROW, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases CARIM Maastricht University, Maastricht, NetherlandsInstitute for Molecular Cardiovascular Research IMCAR, Rheinisch-Westfälische Technische Hogeschool (RWTH) Aachen University, Aachen, GermanyDepartments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsSchool for Oncology and Developmental Biology GROW, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases CARIM Maastricht University, Maastricht, NetherlandsInstitute for Molecular Cardiovascular Research IMCAR, Rheinisch-Westfälische Technische Hogeschool (RWTH) Aachen University, Aachen, GermanyInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, GermanyDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsDepartment of Nutrition and Movement Sciences, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, NetherlandsSchool of Biological Sciences, University of Reading, Health and Life Sciences Building, Whiteknights, Reading, United KingdomDepartments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, NetherlandsLifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound. Given its potential as a therapeutic compound in metabolic inflammatory diseases, in this study, we evaluated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (Ldlr-/) mice that were transplanted with Npc1nih or Npc1wt bone marrow and were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks, thereby creating an extreme model of lysosomal cholesterol-induced metabolic inflammation. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, the inflammatory properties of CD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While CD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after CD treatment, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in vitro in murine BMDMs and macrophages cell lines. Nevertheless, this CD-induced pro-inflammatory profile was time-dependent, as short term exposure to CD did not result in a pro-inflammatory response in BMDM. While CD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using CD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.https://www.frontiersin.org/articles/10.3389/fimmu.2021.716357/full2-hydroxypropyl-β-cyclodextrinmetabolic inflammationcholesterolhepatic inflammationmacrophage