Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 07, 2020
- Source ID
- 10.7554/elife.54877
Entities
People
- Angelo Y. Meliton
- Gökhan M. Mutlu
- Kaitlyn A. Sun
- Lucas M. Kimmig
- Parker S. Woods
- Rengül Cetin-atalay
- Robert B Hamanaka
- Yan Li
Organizations
- American Thoracic Society
- National Heart, Lung, and Blood Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of Environmental Health Sciences
- Respiratory Health Association of Metropolitan Chicago
- United States Department of Defense
- University of Chicago