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

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

doi:10.3389/fimmu.2021.716357

Abstract

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.

Highlights

As one of the most important steroid alcohols of the human body, cholesterol carries a number of essential functions ranging from acting as a key structural component of cell membranes [1] to serving as precursor for bile acids, steroid hormones and vitamin D metabolites [2]
While no effects were observed on plasma (Table 1) and hepatic (Figure 1) cholesterol levels, the ratios of the cholesterol oxidation products 7a-hydroxycholesterol to cholesterol and 27-hydroxycholesterol to cholesterol were both significantly increased in the livers of CD-treated Npc1nih- and Npc1wt-tp Ldlr-/- mice, suggesting increased mobilization of cholesterol (Figures 1B, C)
While CD is able to decrease cellular cholesterol levels, our findings demonstrate that its use in the clinic should be closely monitored especially in patients with a metabolic inflammatory background

Summary

Introduction

As one of the most important steroid alcohols of the human body, cholesterol carries a number of essential functions ranging from acting as a key structural component of cell membranes [1] to serving as precursor for bile acids, steroid hormones and vitamin D metabolites [2] Due to this key cellular function of cholesterol, a highly coordinated extra- and intracellular transport system maintains cholesterol homeostasis at a whole body as well as at a cellular level [3, 4]. Another and more prevalent manner that influences cholesterol homeostasis is via excessive overnutrition, leading to metabolic syndrome and its associated diseases [8] In this context, excessive cholesterol accumulates at locations such as the vessel wall (atherosclerosis) and the liver (non-alcoholic fatty liver disease (NAFLD)) subsequently triggering resident macrophages to evolve into foam cells characterized by lysosomal cholesterol accumulation that induces an undesired inflammatory response, referred to as metabolic inflammation [4, 9]. Taken the prevalence and the severity of these disorders into consideration, efficient therapeutic options aimed at reducing cellular cholesterol levels are needed

Methods

Results

Conclusion