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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.

SUBMITTER: Sun KA

PROVIDER: S-EPMC7185992 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Sun Kaitlyn A KA Li Yan Y Meliton Angelo Y AY Woods Parker S PS Kimmig Lucas M LM Cetin-Atalay Rengül R Hamanaka Robert B RB Mutlu Gökhan M GM

eLife 20200407

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, wh ...[more]

PMID: 32255424

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Project description:Objective: Cooking and heating with coal is the main source of household air pollution in acid rain-plagued areas of China and is a leading contributor to disease burden. In this study, we investigated the adverse effects of exposure to indoor fine particulate matter emission from coal combustion on the expression levels of inflammatory factors in ovalbumin (OVA)-induced mice. Methods: Forty BALB/c male mice were randomly divided into four groups (control group, PM2.5 group, OVA group, and OVA + PM2.5 group; n = 10) and treated with ovalbumin (OVA) or PM2.5, alone or together. Interleukin-4 (IL-4), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-17 (IL-17), transforming growth factor β1 (TGF-β1), and interferon γ (IFN-γ) protein expression levels were measured in bronchoalveolar lavage fluid (BALF). Additionally, serum immunoglobulin (Ig) IgE and IgG1 levels were measured. The mRNA expression levels of IL-7 and IFN-γ in pulmonary tissue were also analyzed. Bronchoalveolar lavage (BAL), inflammatory cell counts, and histopathological examinations were also performed. Results: Exposure to PM2.5 + OVA induced abnormal pathological changes and inflammatory responses in lungs compared to the control. The levels of IL-4, IL-7, IL-8 and IL-17 in BALF from the OVA + PM2.5 group were higher than those in BALF from the control group, OVA group, and PM2.5 group (P < 0.05). PM2.5 plus OVA significantly raised the serum IgE and IgG1 levels compared with the control group. An increasing IL-7 mRNA trend was found among the treatment groups (P < 0.05). The expression level of IFN-γ mRNA was significantly higher in the control group than in the other 3 groups (P < 0.05). Conclusion: Indoor coal PM2.5 was sufficient by itself to cause inflammatory cellular infiltration of pulmonary tissue, leading to organelle injury and physiological structure change. Additionally, it promoted the occurrence and development of asthma by influencing the expression levels of IL-7 and various relevant inflammatory factors (such as IL-4 and IL-8) and changing the equilibrium between Treg and Th17 cells.

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

Publications

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

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