Title: Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response.
Authors: Sun, Kaitlyn A; Li, Yan; Meliton, Angelo Y; Woods, Parker S; Kimmig, Lucas M; Cetin-Atalay, Rengül; Hamanaka, Robert B; Mutlu, Gökhan M
Published In Elife, (2020 04 07)
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 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-/- 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.
PubMed ID: 32255424
MeSH Terms: Animals; Carboxy-Lyases/genetics*; Inflammation*; Macrophages, Alveolar/drug effects; Macrophages, Alveolar/metabolism*; Mice; Mice, Knockout; NF-E2-Related Factor 2/genetics*; Oxygen/metabolism; Particulate Matter/administration & dosage*; RNA-Seq; Signal Transduction; Succinates/metabolism*; Succinates/pharmacology