HIF-1α regulates IL-1β and IL-17 in sarcoidosis
- Wayne State University, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
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
© 2019, Talreja et al.
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.
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HIF-1α regulates IL-1β and IL-17 in sarcoidosis
eLife 8:e44519.
https://doi.org/10.7554/eLife.44519
Further reading
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Background:
Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, this study assessed the impact of both acute and repetitive taVNS on cardiovascular function.
Methods:
In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram readings and vital signs. We compared long-term changes in heart rate, heart rate variability (HRV), QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.
Results:
We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure (ICP). However, repetitive taVNS increased overall HRV and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2 to 4 days after initial treatment (Cohen’s d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, ICP, or HRV. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their modified Rankin Score at the time of discharge.
Conclusions:
Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.
Funding:
The American Association of Neurological Surgeons (ALH), The Aneurysm and AVM Foundation (ALH), The National Institutes of Health R01-EB026439, P41-EB018783, U24-NS109103, R21-NS128307 (ECL, PB), McDonnell Center for Systems Neuroscience (ECL, PB), and Fondazione Neurone (PB).
Clinical trial number:
