Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3

  1. Zeina Salloum
  2. Kristin Dauner
  3. Yun-feng Li
  4. Neha Verma
  5. David Valdivieso-González
  6. Víctor G Almendro-Vedia
  7. John D Zhang
  8. Kiran Nakka
  9. Mei Xi Chen
  10. Jeffrey G McDonald
  11. Chase D Corley
  12. Alexander Sorisky
  13. Bao-Liang Song
  14. Iván López-Montero
  15. Jie Luo
  16. Jeffrey F Dilworth
  17. Xiaohui Zha  Is a corresponding author
  1. Ottawa Hospital Research Institute, Canada
  2. Wuhan University, China
  3. Universidad Complutense de Madrid, Spain
  4. The University of Texas Southwestern Medical Center, United States

Abstract

Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.

Data availability

1. Sequencing data have been deposited in GEO under accession codes:GSE196187, GSE196188, GSE196189.2. All data generated or analysed during this study are included in the manuscript.

The following data sets were generated

Article and author information

Author details

  1. Zeina Salloum

    Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5216-8601
  2. Kristin Dauner

    Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Yun-feng Li

    Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Neha Verma

    2015202040152@whu.edu.cn, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. David Valdivieso-González

    3Departamento Química Física, Universidad Complutense de Madrid, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Víctor G Almendro-Vedia

    3Departamento Química Física, Universidad Complutense de Madrid, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7297-1901
  7. John D Zhang

    Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Kiran Nakka

    Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8418-9343
  9. Mei Xi Chen

    Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Jeffrey G McDonald

    Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Chase D Corley

    Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Alexander Sorisky

    Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Bao-Liang Song

    Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Iván López-Montero

    Departamento Química Física, Universidad Complutense de Madrid, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8131-6063
  15. Jie Luo

    Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Jeffrey F Dilworth

    Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Xiaohui Zha

    Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
    For correspondence
    xzha@ohri.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2873-3073

Funding

Heart and Stroke Foundation of Canada (G-19-0026359)

  • Xiaohui Zha

Canadian Institutes of Health Research (PJT-180504)

  • Jeffrey F Dilworth

NIH Office of the Director (HL020948)

  • Jeffrey G McDonald

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

Reviewing Editor

  1. Jalees Rehman, University of Illinois at Chicago, United States

Version history

  1. Received: January 5, 2023
  2. Accepted: March 13, 2024
  3. Accepted Manuscript published: April 11, 2024 (version 1)
  4. Accepted Manuscript updated: April 15, 2024 (version 2)

Copyright

© 2024, Salloum 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. Zeina Salloum
  2. Kristin Dauner
  3. Yun-feng Li
  4. Neha Verma
  5. David Valdivieso-González
  6. Víctor G Almendro-Vedia
  7. John D Zhang
  8. Kiran Nakka
  9. Mei Xi Chen
  10. Jeffrey G McDonald
  11. Chase D Corley
  12. Alexander Sorisky
  13. Bao-Liang Song
  14. Iván López-Montero
  15. Jie Luo
  16. Jeffrey F Dilworth
  17. Xiaohui Zha
(2024)
Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3
eLife 13:e85964.
https://doi.org/10.7554/eLife.85964

Share this article

https://doi.org/10.7554/eLife.85964

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