Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

Abstract

Particulate matter (PM) air pollution causes cardiopulmonary mortality via macrophage-driven lung inflammation; however, the mechanisms are incompletely understood. RNA-sequencing demonstrated Acod1 (Aconitate decarboxylase 1) as one of the top genes induced by PM in macrophages. Acod1 encodes a mitochondrial enzyme that produces itaconate, which was shown to exert anti-inflammatory effects via NRF2 after LPS. Here, we demonstrate that PM induces Acod1 and itaconate, which reduced mitochondrial respiration via complex II inhibition. Using Acod1-/- mice, we found that Acod1/endogenous itaconate does not affect PM-induced inflammation or NRF2 activation in macrophages in vitro or in vivo. In contrast, exogenous cell permeable itaconate, 4-octyl itaconate (OI) attenuated PM-induced inflammation in macrophages. OI was sufficient to activate NRF2 in macrophages; however, NRF2 was not required for the anti-inflammatory effects of OI. We conclude that the effects of itaconate production on inflammation are stimulus-dependent, and that there are important differences between endogenous and exogenously-applied itaconate.

Data availability

Sequencing data have been deposited in GEO under accession code GSE143881. In addition, source data files have been provided for Figure 1, Figure 6A, 6B and 6C.

The following data sets were generated

Article and author information

Author details

  1. Kaitlyn A Sun

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yan Li

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Angelo Y Meliton

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Parker S Woods

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lucas M Kimmig

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Rengül Cetin-Atalay

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Robert B Hamanaka

    Department of Medicine, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8909-356X
  8. Gökhan M Mutlu

    Medicine, The University of Chicago, Chicago, United States
    For correspondence
    gmutlu@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2056-612X

Funding

National Institute of Environmental Health Sciences (R01ES015024)

  • Gökhan M Mutlu

National Institute of Environmental Health Sciences (U01ES026718)

  • Gökhan M Mutlu

National Institute of Environmental Health Sciences (P30ES027792)

  • Gökhan M Mutlu

National Heart, Lung, and Blood Institute (P01HL14454)

  • Gökhan M Mutlu

National Heart, Lung, and Blood Institute (T32HL007605)

  • Parker S Woods
  • Lucas M Kimmig

National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR066579)

  • Robert B Hamanaka

American Thoracic Society (Unrestritcted Grant)

  • Robert B Hamanaka

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols (72376 and 72465) of the University of Chicago.

Reviewing Editor

  1. Tiffany Horng, ShanghaiTech University, China

Publication history

  1. Received: January 4, 2020
  2. Accepted: April 3, 2020
  3. Accepted Manuscript published: April 7, 2020 (version 1)
  4. Version of Record published: April 27, 2020 (version 2)

Copyright

© 2020, Sun 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. Kaitlyn A Sun
  2. Yan Li
  3. Angelo Y Meliton
  4. Parker S Woods
  5. Lucas M Kimmig
  6. Rengül Cetin-Atalay
  7. Robert B Hamanaka
  8. Gökhan M Mutlu
(2020)
Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response
eLife 9:e54877.
https://doi.org/10.7554/eLife.54877

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