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 considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contraindicating 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 investigated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation. Methods: 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. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, a profound analysis of the inflammatory properties of CD was conducted in macrophages in vitro. Results: While therapeutical administration of CD improved cholesterol mobilization, an overall pro-inflammatory profile was observed, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in bone marrow-derived macrophages (BMDMs) and macrophage 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 BMDMs. Conclusion: 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