HIF-1α regulates IL-1β and IL-17 in sarcoidosis

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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.

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All data generated or analysed during this study are included in the manuscript.

Article and author information

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Jaya Talreja

Department of Internal Medicine, Wayne State University, Detroit, United States

For correspondence
fq0442@wayne.edu

Competing interests
The authors declare that no competing interests exist.
Harvinder Talwar

Department of Internal Medicine, Wayne State University, Detroit, United States

For correspondence
htalwar@med.wayne.edu

Competing interests
The authors declare that no competing interests exist.
Christian Bauerfeld

Department of Pediatrics, Wayne State University, Detroit, United States

For correspondence
cbauerfe@med.wayne.edu

Competing interests
The authors declare that no competing interests exist.
Lawrence I Grossman

Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States

For correspondence
lgrossman@wayne.edu

Competing interests
The authors declare that no competing interests exist.
Kezhong Zhang

Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States

For correspondence
kzhang@med.wayne.edu

Competing interests
The authors declare that no competing interests exist.
Paul Tranchida

Department of Pathology, Wayne State University, Detroit, United States

Competing interests
The authors declare that no competing interests exist.
Lobelia Samavati

Department of Internal Medicine, Wayne State University, Detroit, United States

For correspondence
ay6003@wayne.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3327-2585

Funding

National Heart, Lung, and Blood Institute (R01HL113508)

Lobelia Samavati

American Lung Association

Lobelia Samavati

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The Committee for Investigations Involving Human Subjects at Wayne State University approved the protocol for obtaining alveolar macrophages by bronchoalveolar lavage (BAL) and blood by phlebotomy from control subjects and patients with sarcoidosis.The IRB number for this study is 055208MP4E. Informed consent was obtained from all subjects enrolled for the study.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.