Dimethyl itaconate alleviates the pyroptosis of macrophages through oxidative stress

BMC Immunology

Yan Lu¹  Bing-Bing Jia¹  Guo-Long Cai¹  Zhou-Xin Yang¹  Dong-Yang Guo¹  Jing Yan¹  Shan-Shan Huang² 

[1]Department of Critical Care Medicine, Zhejiang Hospital, 1229 Gudun Road, 310030, Hangzhou, China

[2]The Second Clinical Medical Collage, Zhejiang Chinese Medicine University, 310053, Hangzhou, China

关键词: Dimethyl itaconate;    Pyroptosis;    Macrophages;    Oxidative stress;   

DOI  :  10.1186/s12865-021-00463-3

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY