Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response
Kaitlyn A Sun,
Angelo Y. Meliton,
Parker S Woods,
Lucas M Kimmig,
Robert B. Hamanaka,
Gokhan M Mutlu
Posted 20 Jan 2020
bioRxiv DOI: 10.1101/2020.01.19.911917 (published DOI: 10.7554/eLife.54877)
Posted 20 Jan 2020
Particulate matter (PM) air pollution causing significant cardiopulmonary mortality via macrophage-driven lung inflammation; however, the mechanisms are not completely 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 has been 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 -/- macrophages, we found that Acod1/endogenous itaconate was not required for PM-induced inflammation or NRF2 activation. In contrast to endogenous itaconate, exogenous cell permeable form of itaconate (4-octyl itaconate (OI)) attenuated the PM-induced inflammation and activated NRF2 but 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.
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