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.
Highlights
Sarcoidosis is a systemic granulomatous disease of unknown etiology that is characterized by extensive local inflammation and granuloma formation in different organs with an increase in T-helper type 1 (Th1) mediated cytokine production (Hunninghake et al, 1994; Iannuzzi et al, 2007; Miyara et al, 2006; Rastogi et al, 2011)
Because most of genes in these pathways showed the presence of hypoxia response elements (HREs), we further focused on interrogation of the hypoxia inducible factor (HIF)-pathway
We investigated the role of HIF-isoforms in sarcoid alveolar macrophages and blood monocytes as well as PBMCs
Summary
Sarcoidosis is a systemic granulomatous disease of unknown etiology that is characterized by extensive local inflammation and granuloma formation in different organs with an increase in T-helper type 1 (Th1) mediated cytokine production (Hunninghake et al, 1994; Iannuzzi et al, 2007; Miyara et al, 2006; Rastogi et al, 2011). The sustained p38 activation directly controls expression of several cytokines in sarcoidosis AMs and monocytes and the modulation of p38 regulates T cell responses (Rastogi et al, 2011; Talreja et al, 2016). Talreja et al have identified which genes and proteins control this inflammatory response in immune cells from the lungs and blood of sarcoidosis patients. Immune cells in the lungs of sarcoidosis patients were found to have higher levels of hypoxia inducible factor (HIF) – a gene-regulating protein that controls the uptake and metabolism of oxygen in mammals. We applied a combination of transcriptional and functional approaches to investigate the role of HIF-1a in mediating the inflammatory immune response in AMs, monocytes, and PBMCs of sarcoidosis patients as compared to healthy controls. RNA (siRNA) decreased IL-1b in sarcoidosis AMs, while decreased HIF-1a expression in PBMCs decreased IL-1b and IL-17 in response to anti-CD3 challenge
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