Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, United States.
Department of Pediatrics, Division of Critical Care, Wayne State University School of Medicine and Detroit Medical Center, Detroit, United States.
Elife. 2019 May 1;8:e44519. doi: 10.7554/eLife.44519.
Sarcoidosis is a complex systemic granulomatous disease of unknown etiology characterized by the presence of activated macrophages and Th1/Th17 effector cells. Data mining of our RNA-Seq analysis of CD14monocytes showed enrichment for metabolic and hypoxia inducible factor (HIF) pathways in sarcoidosis. Further investigation revealed that sarcoidosis macrophages and monocytes exhibit higher protein levels for HIF-α isoforms, HIF-1β, and their transcriptional co-activator p300 as well as glucose transporter 1 (Glut1). In situ hybridization of sarcoidosis granulomatous lung tissues showed abundance of HIF-1α in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1β and IL-17 since targeted down regulation of HIF-1α via short interfering RNA or a HIF-1α inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1α levels and modified cytokine production. These data suggest that increased activity of HIF-α isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.
结节病是一种病因不明的复杂系统性肉芽肿性疾病，其特征是存在活化的巨噬细胞和 Th1/Th17 效应细胞。我们对 CD14+单核细胞的 RNA-Seq 分析进行的数据挖掘显示，结节病中存在代谢和缺氧诱导因子 (HIF) 途径的富集。进一步的研究表明，结节病巨噬细胞和单核细胞表现出更高的 HIF-α 同工型、HIF-1β 及其转录共激活因子 p300 以及葡萄糖转运蛋白 1 (Glut1) 的蛋白水平。结节病肉芽肿性肺组织的原位杂交显示，在肉芽肿的中心有大量的 HIF-1α。HIF 同工型的丰度与升高的 IL-1β 和 IL-17 有关，因为通过短发夹 RNA 或 HIF-1α 抑制剂靶向下调 HIF-1α 可降低其产生。使用溶酶体抑制剂氯喹进行的药理学干预降低了溶酶体相关蛋白 2 (LAMP2) 和 HIF-1α 水平，并改变了细胞因子的产生。这些数据表明，HIF-α 同工型的活性增加调节了结节病中的 Th1/Th17 介导的炎症。
