Dimethyl itaconate alleviates the pyroptosis of macrophages through oxidative stress

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Macrophages are crucial innate immune cells involved in disease pathophysiology.
• Pyroptosis is a pro-inflammatory form of programmed cell death in macrophages, essential for host defense.
• Dimethyl itaconate (DI), an itaconic acid analog, exhibits anti-inflammatory properties, but its role in macrophage pyroptosis remains unclear.

Purpose of the Study:

• To investigate the effect of dimethyl itaconate (DI) on lipopolysaccharide (LPS) + adenosine triphosphate (ATP)-induced macrophage pyroptosis.
• To elucidate the molecular mechanisms underlying DI's action on macrophage pyroptosis.

Main Methods:

• Macrophage pyroptosis model induced by LPS + ATP.
• Treatment with varying concentrations of dimethyl itaconate (DI).
• RNA-sequencing, real-time quantitative polymerase chain reaction (RT-qPCR), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.
• Assessment of oxidative stress markers and Nrf2 protein.

Main Results:

• 0.25 mM DI significantly ameliorated macrophage pyroptosis and downregulated interleukin (IL)-1β expression.
• DI treatment altered the expression of oxidative stress-related genes (Gclc, Gss) and inflammation-related genes (IL-12β, IL-1β).
• DI modulated key inflammatory and immune signaling pathways, including TNF, Jak, Toll-like receptor, and IL-17.
• N-acetyl-L-cysteine (NAC) reversed DI's effects, and Nrf2 was identified as a key regulator in DI's mechanism.

Conclusions:

• Dimethyl itaconate (DI) effectively alleviates macrophage pyroptosis.
• DI exerts its protective effects by modulating oxidative stress pathways, involving the Nrf2 protein.
• These findings highlight DI as a potential therapeutic agent for inflammatory diseases characterized by pyroptosis.