1. Immunology and Inflammation
  2. Medicine
Download icon

Methotrexate attenuates vascular inflammation through an adenosine-microRNA dependent pathway

  1. Dafeng Yang
  2. Stefan Haemmig
  3. Haoyang Zhou
  4. Daniel Pérez-Cremades
  5. Xinghui Sun
  6. Lei Chen
  7. Jie Li
  8. Jorge Haneo-Mejia
  9. Tianlun Yang
  10. Ivana Hollan
  11. Mark W Feinberg  Is a corresponding author
  1. Brigham and Women's Hospital/Harvard Medical School, United States
  2. Central South University, China
  3. Xiangya Hospital, Central South University, China
  4. University of Pennsylvania, United States
Research Article
  • Cited 0
  • Views 204
  • Annotations
Cite this article as: eLife 2021;10:e58064 doi: 10.7554/eLife.58064

Abstract

Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b (MiR-181b) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating MiR-181b expression. Both systemic and endothelial-specific MiR-181a2b2-deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a MiR-181a2b2-dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4-MiR-181b signaling cascade. These findings establish an essential role of endothelial MiR-181b in controlling vascular inflammation and that restoring MiR-181b in ECs by high dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.

Article and author information

Author details

  1. Dafeng Yang

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Stefan Haemmig

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Haoyang Zhou

    Cardiovascular, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Daniel Pérez-Cremades

    Medicine, Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xinghui Sun

    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lei Chen

    Cardiology, Xiangya Hospital, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jie Li

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jorge Haneo-Mejia

    Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Tianlun Yang

    Cardiology, Xiangya Hospital, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Ivana Hollan

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Mark W Feinberg

    Medicine/Cardiology, Brigham and Women's Hospital/Harvard Medical School, Boston, United States
    For correspondence
    mfeinberg@bwh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9523-3859

Funding

National Institutes of Health (HL115141)

  • Mark W Feinberg

National Institutes of Health (HL134849)

  • Mark W Feinberg

American Heart Association (18SFRN33900144)

  • Mark W Feinberg

American Heart Association (18POST34030395)

  • Stefan Haemmig

Falk Foundation

  • Mark W Feinberg

National Natural Science Foundation of China

  • Tianlun Yang

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

Ethics

Animal experimentation: All mice were maintained under SPF conditions at an American Association for the Accreditation of Laboratory Animal Care-accredited animal facility at the Brigham and Women's Hospital (protocol #2016N000182). All animal protocols were approved by the Institutional Animal Care and Use Committee at Harvard Medical School, Boston, MA and conducted in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals.

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Received: April 20, 2020
  2. Accepted: December 31, 2020
  3. Accepted Manuscript published: January 8, 2021 (version 1)

Copyright

© 2021, Yang 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.

Metrics

  • 204
    Page views
  • 30
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    2. Medicine
    Danielle Janosevic et al.
    Research Article

    Sepsis is a dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single-cell RNA-sequencing in a murine endotoxemia model revealed the involvement of various cell populations to be temporally organized and highly orchestrated. Endothelial and stromal cells were the first responders. At later time points, epithelial cells upregulated immune-related pathways while concomitantly downregulating physiological functions such as solute homeostasis. Sixteen hours after endotoxin, there was global cell–cell communication failure and organ shutdown. Despite this apparent organ paralysis, upstream regulatory analysis showed significant activity in pathways involved in healing and recovery. This rigorous spatial and temporal definition of murine endotoxemia will uncover precise biomarkers and targets that can help stage and treat human sepsis.

    1. Immunology and Inflammation
    2. Medicine
    Kelsey E Huntington et al.
    Short Report

    Although the range of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is variable, cytokine storm is observed in a subset of symptomatic individuals. To further understand the disease pathogenesis and, consequently, to develop an additional tool for clinicians to evaluate patients for presumptive intervention we sought to compare plasma cytokine levels between a range of donor and patient samples grouped by a COVID-19 Severity Score (CSS) based on need for hospitalization and oxygen requirement. Here we utilize a mutual information algorithm that classifies the information gain for CSS prediction provided by cytokine expression levels and clinical variables. Using this methodology, we found that a small number of clinical and cytokine expression variables are predictive of presenting COVID-19 disease severity, raising questions about the mechanism by which COVID-19 creates severe illness. The variables that were the most predictive of CSS included clinical variables such as age and abnormal chest x-ray as well as cytokines such as macrophage colony-stimulating factor (M-CSF), interferon-inducible protein 10 (IP-10) and Interleukin-1 Receptor Antagonist (IL-1RA). Our results suggest that SARS-CoV-2 infection causes a plethora of changes in cytokine profiles and that particularly in severely ill patients, these changes are consistent with the presence of Macrophage Activation Syndrome and could furthermore be used as a biomarker to predict disease severity.