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

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Particulate matter (PM) air pollution causing significant cardiopulmonary mortality via macrophage-driven lung inflammation; however, the mechanisms are not completely understood. RNA-sequencing demonstrated <jats:italic>Acod1</jats:italic> (<jats:italic>Aconitate decarboxylase 1</jats:italic>) as one of the top genes induced by PM in macrophages. <jats:italic>Acod1</jats:italic> 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 <jats:italic>Acod1</jats:italic><jats:sup>-/-</jats:sup> 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.</jats:p>

Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

“…Moreover, LPS-stimulated microglia M1 polarization was reduced with DI treatment. However, exogenous addition of the itaconate derivative did not result in metabolic production of endogenous itaconate (38). As a more powerful version of itaconate, the dimethyl derivative exhibits increased electrophilicity that may not truly reflect the innate biological function of the endogenous compound.…”