Departments of Genetics and Cell Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht, Maastricht, Netherlands.
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.
Front Immunol. 2021 Aug 20;12:716357. doi: 10.3389/fimmu.2021.716357. eCollection 2021.
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 and . The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout ( ) mice that were transplanted with or 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 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 and a strong increase in cytokine release and inflammatory gene expression 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.
生活方式和遗传引起的胆固醇代谢紊乱与炎症等多种病理过程相关，这些过程表明胆固醇水平过高会产生有害影响。在这种情况下，由于能够增加胆固醇的溶解度，2-羟丙基-β-环糊精（CD）越来越被认为是一种降低细胞胆固醇水平的新型药物化合物。然而，最近的研究报告称，在使用 CD 后出现了不良反应，这使得该化合物的临床应用受到质疑。鉴于其在代谢性炎症疾病中的治疗潜力，在这项研究中，我们评估了 CD 在胆固醇诱导的代谢性炎症中的炎症作用。首先，我们在低密度脂蛋白受体敲除（）小鼠中研究了 CD 的炎症和胆固醇耗竭作用，这些小鼠接受了骨髓移植，分别接受了普通饮食或高脂肪、高胆固醇（HFC）饮食 12 周，从而建立了溶酶体胆固醇诱导的代谢性炎症的极端模型。在最后三周，这些小鼠每天接受皮下注射生理盐水或 CD。随后，我们在两种巨噬细胞系和鼠骨髓来源的巨噬细胞（BMDM）中研究了 CD 的炎症特性。虽然 CD 给药可改善 BMDM 溶酶体外的胆固醇动员，但在 CD 处理后观察到总体促炎表型，这表现在肝炎症增加和细胞因子释放以及炎性基因表达在鼠 BMDM 和巨噬细胞系中强烈增加。然而，这种 CD 诱导的促炎表型是时间依赖性的，因为短期暴露于 CD 不会导致 BMDM 产生促炎反应。虽然 CD 发挥了所需的胆固醇耗竭作用，但它的炎症作用取决于暴露时间。因此，在临床中使用 CD，特别是在代谢性炎症的情况下，应密切监测，因为它可能会导致不良的、促炎的副作用。
