PMID- 34489968
OWN - NLM
STAT- MEDLINE
DCOM- 20211223
LR  - 20211223
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Pro-Inflammatory Implications of 2-Hydroxypropyl-beta-cyclodextrin Treatment.
PG  - 716357
LID - 10.3389/fimmu.2021.716357 [doi]
LID - 716357
AB  - 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-beta-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 Npc1(nih) or Npc1(wt) 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.
CI  - Copyright (c) 2021 Houben, Yadati, de Kruijf, Gijbels, Luiken, van Zandvoort, 
      Kapsokalyvas, Lutjohann, Westerterp, Plat, Leake and Shiri-Sverdlov.
FAU - Houben, Tom
AU  - Houben T
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
FAU - Yadati, Tulasi
AU  - Yadati T
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
FAU - de Kruijf, Robbin
AU  - de Kruijf R
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
FAU - Gijbels, Marion J J
AU  - Gijbels MJJ
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
FAU - Luiken, Joost J F P
AU  - Luiken JJFP
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
FAU - van Zandvoort, Marc
AU  - van Zandvoort M
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
AD  - School for Oncology and Developmental Biology GROW, School of Nutrition and 
      Translational Research in Metabolism (NUTRIM) and School for Cardiovascular 
      Diseases CARIM Maastricht University, Maastricht, Netherlands.
AD  - Institute for Molecular Cardiovascular Research IMCAR, Rheinisch-Westfalische 
      Technische Hogeschool (RWTH) Aachen University, Aachen, Germany.
FAU - Kapsokalyvas, Dimitris
AU  - Kapsokalyvas D
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
AD  - School for Oncology and Developmental Biology GROW, School of Nutrition and 
      Translational Research in Metabolism (NUTRIM) and School for Cardiovascular 
      Diseases CARIM Maastricht University, Maastricht, Netherlands.
AD  - Institute for Molecular Cardiovascular Research IMCAR, Rheinisch-Westfalische 
      Technische Hogeschool (RWTH) Aachen University, Aachen, Germany.
FAU - Lutjohann, Dieter
AU  - Lutjohann D
AD  - Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital 
      Bonn, Bonn, Germany.
FAU - Westerterp, Marit
AU  - Westerterp M
AD  - Department of Pediatrics, University of Groningen, University Medical Center 
      Groningen, Groningen, Netherlands.
FAU - Plat, Jogchum
AU  - Plat J
AD  - Department of Nutrition and Movement Sciences, School for Nutrition and 
      Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, 
      Netherlands.
FAU - Leake, David
AU  - Leake D
AD  - School of Biological Sciences, University of Reading, Health and Life Sciences 
      Building, Whiteknights, Reading, United Kingdom.
FAU - Shiri-Sverdlov, Ronit
AU  - Shiri-Sverdlov R
AD  - Departments of Genetics and Cell Biology, School of Nutrition and Translational 
      Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, 
      Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210820
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Biomarkers)
RN  - 0 (Lipids)
RN  - 0 (Receptors, LDL)
RN  - 1I96OHX6EK (2-Hydroxypropyl-beta-cyclodextrin)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - 2-Hydroxypropyl-beta-cyclodextrin/adverse effects/*pharmacology
MH  - Animals
MH  - Biomarkers
MH  - Cell Line
MH  - Cholesterol/blood/metabolism
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression Regulation/drug effects
MH  - Inflammation/*etiology/metabolism/pathology
MH  - Lipid Metabolism/drug effects
MH  - Lipids/blood
MH  - Liver/drug effects/metabolism/pathology
MH  - Lysosomes/metabolism
MH  - Macrophages/drug effects/immunology/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Receptors, LDL/genetics/metabolism
PMC - PMC8417873
OTO - NOTNLM
OT  - 2-hydroxypropyl-beta-cyclodextrin
OT  - cholesterol
OT  - hepatic inflammation
OT  - macrophage
OT  - metabolic inflammation
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/09/08 06:00
MHDA- 2021/12/24 06:00
PMCR- 2021/01/01
CRDT- 2021/09/07 07:43
PHST- 2021/05/28 00:00 [received]
PHST- 2021/07/23 00:00 [accepted]
PHST- 2021/09/07 07:43 [entrez]
PHST- 2021/09/08 06:00 [pubmed]
PHST- 2021/12/24 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.716357 [doi]
PST - epublish
SO  - Front Immunol. 2021 Aug 20;12:716357. doi: 10.3389/fimmu.2021.716357. eCollection 
      2021.