HIF-1α regulates IL-1β and IL-17 in sarcoidosis
Abstract
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 CD14+monocytes 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2019
- Source ID
- 10.7554/elife.44519
Entities
People
- Christian Bauerfeld
- Harvinder Talwar
- Jaya Talreja
- Kezhong Zhang
- Lawrence I. Grossman
- Lobelia Samavati
- Paul Tranchida
Organizations
- American Lung Association
- National Heart, Lung, and Blood Institute
- United States Department of Defense
- Wayne State University
- Wayne State University School of Medicine