AUTHOR=Houben Tom , Yadati Tulasi , de Kruijf Robbin , Gijbels Marion J. J. , Luiken Joost J. F. P. , van Zandvoort Marc , Kapsokalyvas Dimitris , Lütjohann Dieter , Westerterp Marit , Plat Jogchum , Leake David , Shiri-Sverdlov Ronit 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.716357

DOI=10.3389/fimmu.2021.716357

ISSN=1664-3224

ABSTRACT=<p>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 <italic>in vivo</italic> and <italic>in vitro</italic>. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (<italic>Ldlr<sup>-/</sup></italic>) mice that were transplanted with <italic>Npc1<sup>nih</sup></italic> or <italic>Npc1<sup>wt</sup></italic> 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 <italic>in vitro</italic> 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 <italic>in vivo</italic> and a strong increase in cytokine release and inflammatory gene expression <italic>in vitro</italic> 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.</p>