Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response
- The University of Chicago, United States
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.
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Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory responseNCBI Gene Expression Omnibus, GSE143881.
Article and author information
Author details
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.
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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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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