IDO1 regulation of SR-BI and cholesterol homeostasis in macrophages

炎症是一种基本的生物学过程，在免疫反应中起着关键作用。然而， 失控的慢性炎症是许多人类疾病的根源，包括新陈代谢 疾病、肥胖、胰岛素抵抗、糖尿病、高血压和动脉粥样硬化。巨噬细胞激活作用 在炎症中起中心作用，在病原体感染期间调节宿主防御，并维持组织 动态平衡。最近的研究表明，巨噬细胞的功能受到脂质代谢的影响。 巨噬细胞脂质摄取、代谢和清除失衡导致组织转分化 导致高脂血症和代谢综合征。例如，巨噬细胞和衍生泡沫细胞 动脉粥样硬化的特征。与脂质稳态和代谢相关的信号机制 巨噬细胞很复杂，人们对它知之甚少。这项提案的主要目标是调查 炎症状态下巨噬细胞的胆固醇稳态机制。具体而言，HDLR-SR-BI(SR-BI)、 富含胆固醇的高密度脂蛋白的受体，促进高密度脂蛋白-胆固醇酯的选择性输送到肝脏。它 通过高密度脂蛋白代谢促进动脉粥样硬化的保护。SR-BI也在巨噬细胞中表达，并调节脂质 动态平衡。在初步研究中，我们观察到巨噬细胞中SR-BI的表达下调 在内毒素刺激下，这可能是通过吲哚-2，3-双加氧酶1(IDO1)调节的。我们发现 IDO1及其下游分解代谢产物犬尿氨酸(KYN)也在内毒素刺激的巨噬细胞和 抑制IDO1逆转了内毒素诱导的SR-BI下调，提示IDO1在SR-BI中可能起作用。 巨噬细胞中BI表达与胆固醇动态平衡。值得注意的是，KYN是芳基烃的配体 受体(AhR)，调节基因毒性应激和炎症反应。在这里，我们提出了生化和 基于细胞的实验研究IDO1和Kyn-AhR信号在SR-BI表达和表达中的作用 巨噬细胞中的胆固醇稳态(目标1)。在目标2中，我们建议研究IDO1在 肝脏炎症、库普弗细胞(肝脏内停留的巨噬细胞)激活、SR-BI表达和胆固醇 以去卵巢(OVX)大鼠为动物模型的体内动态平衡。总体而言，我们的研究将导致 与SR-BI表达和胆固醇稳态相关的新信号通路的发现 巨噬细胞处于炎症状态。除了解决一个重要的科学问题外，这项提议还将 也有助于丰富学生(特别是本科生)在UTA的研究经验，UTA是一个为少数民族服务的机构 机构。 1

Inflammation is a fundamental biological process that plays key roles in immune response. However, uncontrolled, and chronic inflammation are the root causes of many human diseases including metabolic disorders, obesity, insulin resistance, diabetes, hypertension, and atherosclerosis. Macrophage activation plays a central role in inflammation, regulates the host defense during pathogenic infection, and maintain tissue homeostasis. Recent studies indicate that macrophage functions are influenced by lipid metabolism.10-15 The imbalance in lipid uptake, metabolism, and removal in macrophages cause tissue trans-differentiation contributing to hyperlipidemia and metabolic syndrome. For example, macrophages and derived foams cells are the hallmarks of atherosclerosis. The signaling mechanism associated with lipid homeostasis and metabolism in macrophages is complex and poorly understood. The primary goal of this proposal is to investigate the cholesterol homeostasis mechanism in macrophages under inflammation. In particular, HDLR-SR-BI (SR-BI), a receptor for the cholesterol-rich HDL, facilitates the selective delivery of HDL-cholesteryl ester to the liver. It promotes atheroprotection via HDL metabolism. SR-BI is also expressed in in macrophages and regulates lipid homeostasis. In a preliminary study, we observed that the SR-BI expression is downregulated in macrophages upon LPS stimulation, and this is potentially regulated viaIndoleamine-2,3-dioxygenase 1 (IDO1). We found that IDO1 and its down-stream catabolite, kynurenine (KYN), are also elevated in LPS-stimulated macrophages and inhibition of IDO1 reversed the LPS-induced downregulation of SR-BI, suggesting potential role of IDO1 in SR- BI expression and cholesterol homeostasis, in macrophages. Notably, KYN is a ligand for aryl hydrocarbon receptor (AhR) which regulates genotoxic stress and inflammatory response. Here, we propose biochemical and cell-based experiments to investigate the roles of IDO1 and KYN-AhR signaling in SR-BI expression and cholesterol homeostasis, in macrophages (aim 1). In the aim 2, we propose to investigate the roles of IDO1 in hepatic inflammation, Kupffer cells (resident macrophage in liver) activation, SR-BI expression, and cholesterol homeostasis in vivo using ovariectomized (OVX) rat as animal model. Overall, our studies will lead to the discovery of novel signaling pathways associated with SR-BI expression and cholesterol homeostasis in macrophages under inflammation. In addition to addressing an important scientific problem, this proposal will also serve to enrich student (especially undergraduates) research experiences at UTA, a minority-serving institution. 1