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

  1. Jaya Talreja

    Department of Internal Medicine, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Harvinder Talwar

    Department of Internal Medicine, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Christian Bauerfeld

    Department of Pediatrics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lawrence I Grossman

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kezhong Zhang

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Paul Tranchida

    Department of Pathology, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. 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.
    ORCID icon "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.

Reviewing Editor

  1. Jos WM van der Meer, Radboud University Medical Centre, Netherlands

Version history

  1. Received: December 19, 2018
  2. Accepted: April 3, 2019
  3. Accepted Manuscript published: April 4, 2019 (version 1)
  4. Accepted Manuscript updated: May 1, 2019 (version 2)
  5. Version of Record published: May 8, 2019 (version 3)

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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  1. Jaya Talreja
  2. Harvinder Talwar
  3. Christian Bauerfeld
  4. Lawrence I Grossman
  5. Kezhong Zhang
  6. Paul Tranchida
  7. Lobelia Samavati
(2019)
HIF-1α regulates IL-1β and IL-17 in sarcoidosis
eLife 8:e44519.
https://doi.org/10.7554/eLife.44519

Further reading

    1. Epidemiology and Global Health
    2. Medicine
    Jeffrey Thompson, Yidi Wang ... Ulrich H von Andrian
    Research Article Updated

    Background:

    Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

    Methods:

    A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.

    Results:

    A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

    Conclusions:

    Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.

    Funding:

    This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).

    1. Medicine
    Runze Yang, Tianhao Xu ... Weili Fu
    Tools and Resources Updated

    Background:

    To systematically identify cell types in the human ligament, investigate how ligamental cell identities, functions, and interactions participated in the process of ligamental degeneration, and explore the changes of ligamental microenvironment homeostasis in the disease progression.

    Methods:

    Using single-cell RNA sequencing and spatial RNA sequencing of approximately 49,356 cells, we created a comprehensive cell atlas of healthy and degenerated human anterior cruciate ligaments. We explored the variations of the cell subtypes’ spatial distributions and the different processes involved in the disease progression, linked them with the ligamental degeneration process using computational analysis, and verified findings with immunohistochemical and immunofluorescent staining.

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    Funding:

    This study was funded by the National Natural Science Foundation of China (81972123, 82172508, 82372490) and 1.3.5 Project for Disciplines of Excellence of West China Hospital Sichuan University (ZYJC21030, ZY2017301).