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Dimethyl itaconate alleviates the pyroptosis of macrophages through oxidative stress.

ABSTRACT: Macrophages are involved in the pathophysiology of many diseases as critical cells of the innate immune system. Pyroptosis is a form of macrophage death that induces cytokinesis of phagocytic substances in the macrophages, thereby defending against infection. Dimethyl itaconate (DI) is an analog of itaconic acid with anti-inflammatory effects. However, the effect of dimethyl itaconate on macrophage pyroptosis has not been elucidated clearly. Thus, the present study aimed to analyze the effect of DI treatment on a macrophage pyroptosis model (Lipopolysaccharide, LPS + Adenosine Triphosphate, ATP). The results showed that 0.25 mM DI ameliorated macrophage pyroptosis and downregulated interleukin (IL)-1β expression. Then, real-time quantitative polymerase chain reaction (RT-qPCR) was used to confirm the result of RNA-sequencing of the upregulated oxidative stress-related genes (Gclc and Gss) and downregulated inflammation-related genes (IL-12β and IL-1β). In addition, Gene Ontology (GO) enrichment analysis showed that differential genes were associated with transcript levels and DNA replication. Kyoto encyclopedia of genes and genomes (KEGG) enrichment showed that signaling pathways, such as tumor necrosis factor (TNF), Jak, Toll-like receptor and IL-17, were altered after DI treatment. N-acetyl-L-cysteine (NAC) reversed the DI effect on the LPS + ATP-induced macrophage pyroptosis and upregulated the IL-1β expression. Oxidative stress-related protein Nrf2 is involved in the DI regulation of macrophage pyroptosis. Taken together, these findings suggested that DI alleviates the pyroptosis of macrophages through oxidative stress.

SUBMITTER: Huang SS

PROVIDER: S-EPMC8573905 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Dimethyl itaconate alleviates the pyroptosis of macrophages through oxidative stress.

Huang Shan-Shan SS Guo Dong-Yang DY Jia Bing-Bing BB Cai Guo-Long GL Yan Jing J Lu Yan Y Yang Zhou-Xin ZX

BMC immunology 20211108 1

Macrophages are involved in the pathophysiology of many diseases as critical cells of the innate immune system. Pyroptosis is a form of macrophage death that induces cytokinesis of phagocytic substances in the macrophages, thereby defending against infection. Dimethyl itaconate (DI) is an analog of itaconic acid with anti-inflammatory effects. However, the effect of dimethyl itaconate on macrophage pyroptosis has not been elucidated clearly. Thus, the present study aimed to analyze the effect of ...[more]

PMID: 34749650

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Project description:To explore the potential protective effect of resveratrol (RES) on cold-exposed broilers, 360 21-day-old broilers were equally divided into 5 groups with 6 replicates. A control (CON) group was reared at the normal feeding temperature and received a basal diet, and 4 cold exposure (8 ± 1°C for 10 h/d from d 29 to 42) groups were fed the basal diet with 0 (CE), 250 (CE + RES250), 500 (CE + RES500), and 750 (CE + RES750) mg/kg RES from d 22 to 42. Broilers were slaughtered on d 42 and heart tissues were collected to measure the relevant indexes. The results showed that heart tissues of all CE-broilers had inflammatory cell infiltrations, and dietary RES supplementation reduced this phenomenon. Compared to CON group, the concentrations of MDA and H2O2 were increased and activities of SOD and CAT were decreased in all CE-broilers (P < 0.05). mRNA expression of genes related to endoplasmic reticulum (ER) stress (GRP78, IRE1, PERK, EIF-2α, ATF4, ATF6, and CHOP), pyroptosis (NLRP3, ASC, Caspase1, GSDME, IL-18, and IL-1β), and proinflammation (TNF-α, IFN-γ, IL-2, and IL-6) was upregulated and that of ant-inflammatory cytokines (IL-4 and IL-10) was downregulated in CE and all CE + RES groups compared to CON group (P < 0.05). Compared to CE group, the activities of SOD and CAT and mRNA expression of anti-inflammatory genes were increased (P < 0.05), and concentrations of MDA and H2O2 and mRNA expression of ER stress, pyroptosis and proinflammatory genes were reduced (P < 0.05) in 3 CE + RES groups. Additionally, protein levels of PERK, ATF4, CHOP, NLRP3, Caspase1, GSDMD, IL-18, IL-1β, TNF-α, and IL-10 were similar in their mRNA expression. Overall, cold exposure caused oxidative stress and ER stress, and induced pyroptosis and inflammatory response, resulting in heart injury in broilers, and dietary RES addition reduced heart damage by enhancing antioxidant defense function. This study indicates that RES can be a feed additive to alleviate cold exposure-induced heart injury in broilers, and a 500 mg RES/kg diet is the optimal supplemental level.

Dataset Information

Dimethyl itaconate alleviates the pyroptosis of macrophages through oxidative stress.

Publications

Dimethyl itaconate alleviates the pyroptosis of macrophages through oxidative stress.

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