The image, inspired by drawbridges of Saint Petersburg, depicts itaconate disrupting the tricarboxylic acid (TCA) cycle flow. [© Aleksandra Ziminova]
The image, inspired by drawbridges of Saint Petersburg, depicts itaconate disrupting the tricarboxylic acid (TCA) cycle flow. [© Aleksandra Ziminova]

An international group of scientists from the U.S., Canada, Germany, and Russia has shown that itaconate can suppress the proinflammatory activity of macrophages. The substance is released in large quantities by macrophages themselves, but until now its role remained poorly studied. 

Now scientists have found evidence that itaconate acts as an antioxidant and anti-inflammatory agent. These properties make itaconate promising for the treatment of pathologies caused by excessive inflammation or oxidative stress. Such conditions may be associated with cardiac ischemia, metabolic disorders, and perhaps autoimmune diseases. The study (“Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation”) was published in Cell Metabolism.

The work, which united scientists from Washington University in St. Louis, ITMO University, McGill University, and the Max Planck Institute of Immunobiology and Epigenetics, was based on the study of macrophages, which play a critical role in fighting pathogens. An important feature of macrophages is their ability to switch between different states depending on the concentration of various substances in the body. In total, there are three such states: M0, neutral; M1, proinflammatory; and M2, anti-inflammatory.

M1 macrophages arrive first to fight the infection. As they begin to swallow viruses and bacteria, an intense inflammatory process kicks in. This process may adversely affect the entire organism if the macrophages become overly diligent. Inflammation consumes the energy resources of the organism and can lead to numerous complications or even death. Thus, to mitigate the negative consequences of the immune response, it is important to understand that the excessive proinflammatory effect of macrophages can be reduced.

An in-depth study of macrophage metabolism during their transition from the inactive to proinflammatory state helped researchers identify the substance that could suppress macrophage-related inflammations. Describing the working mechanism of this substance, called itaconate, became possible due to a complex map of metabolic pathways in macrophages that was developed by the group.

Itaconate is produced by macrophages when they switch from the M0 inactive state to the M1 proinflammatory state. If the concentration of this substance increases to a defined limit, macrophage activation falls.

“Itaconate sets the bar controlling M1 macrophage formation,” says Alexey Sergushichev, one of the authors of the paper and Ph.D. student at ITMO University. “Without this substance, the inflammation would increase more than required. In the future, with the help of itaconate, it will be possible to artificially manipulate the transition of macrophages from M0 to M1, meaning the possibility of restraining inflammations. The influence of itaconate on macrophages is a delicate mechanism that can ensure high selectivity of the immune system regulation.”

“Noteworthy, itaconate acts as an antioxidant and anti-inflammatory agent,” adds Vicky Lampropoulou, the lead author of the paper and researcher at the laboratory of Maxim Artyomov at Washington University in St. Louis. “At the same time, itaconate is naturally produced by mammalian immune cells. These features make it attractive for use in adjuvant therapy for numerous diseases, in which excessive inflammation and oxidative stress associate with pathology, like heart ischemia, metabolic disorders, and perhaps even autoimmunity.”