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, HPBCD 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 HPBCD 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 HPBCD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of HPBCD 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 HPBCD subcutaneously. Subsequently, the inflammatory properties of HPBCD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While HPBCD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after HPBCD 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 HPBCD-induced pro-inflammatory profile was time-dependent, as short term exposure to HPBCD did not result in a pro-inflammatory response in BMDM. While HPBCD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using HPBCD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.
Tom Houben, Tulasi Yadati, Robbin De Kruijf, Marion Jj Gijbels, J Luiken, Marc Van Zandvoort, Dimitris Kapsokalyvas, Dieter Lütjohann, Marit Westerterp, Jogchum Plat, David Leake, Ronit Shiri-Sverdlov (2021). Pro-inflammatory implications of 2-hydroxypropyl-β-cyclodextrin treatment . Front. Immunol. 12:716357. doi: 10.3389/fimmu.2021.716357