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

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.