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July 13 | Innovation

Itaconate "divorces" macrophages fascinated by the attack

The international team of scientists from the USA, Canada, Germany and Russia found a substance in the human body that can inhibit the proinflammatory action of macrophages - immune system cells, reported on the website of ITMO University. Substance known as itaconate, is produced by the body in large quantities in cells of macrophages, but previously its role was not studied enough. The scientists discovered that itaconate had antioxidant and anti-inflammatory action. These properties make itaconate attractive for using in the treatment of pathologies occurring with excessive inflammation or oxidative effect, such as coronary heart disease, liver and kidney disease, and metabolic disorders and may be even autoimmune diseases. The article with the results of the study was published in Cell Metabolism journal.

The research involved scientists from Washington University in St.Louis (the USA), ITMO University (Russia), McGill University (Canada) and the Institute of Immunobiology and Epigenetics Max Planck Society (Germany) and was based on the study of macrophages - immune cells responsible for the elimination of pathogens and foreign particles in the body. A feature of macrophages is their ability to move in different states depending on the concentration of certain substances in the body. There are three states: M0 - non-activated, M1 – proinflammatory and M2 - anti-inflammatory.

M1-macrophages are the first to arrive to fight the infection and begin to destroy viruses and bacteria, trapped in the body. Thus there is an intense inflammatory process, which may adversely affect the whole body, if the macrophages are carried away. Inflammatory processes consume energy resources of the organism, which can lead to the development of additional complications, including death. In order to mitigate the negative effects of the fight of immune system against causative agent, it is important to understand how it is possible to reduce its excessive pro-inflammatory action.

Macrophages are a type of white blood cell that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the types of proteins specific of healthy body cells on its surface in a process called phagocytosis. These large phagocytes are found in essentially all tissues, where they patrol for potential pathogens by amoeboid movement. They take various forms (with various names) throughout the body (e.g., histiocytes, Kupffer cells, alveolar macrophages, microglia, and others), but all are part of the mononuclear phagocyte system. Besides phagocytosis, they play a critical role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes. For example, they are important as antigen presenters to T cells. In humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections.

The scientists discovered a substance in the metabolism of macrophages called itaconate and capable to inhibit their activity. It became possible due to thorough study of the transition of cells from the non-activated state to a pro-inflammatory.

To identify the substance and describe its mechanism of action was turned possible due to the map of metabolic pathways in these immune cells.


Itaconate was produced by macrophages themselves, during the moving from an inactive state M0 to proinflammatory M1. If the concentration of this substance increases up to a certain limit, process of macrophage activation will slow down. "Itaconate exposes a certain bar, holding back the formation of M1-macrophages, - Alexey Sergushichev, one of the authors, postgraduate at ITMO University, says. - Without this substance the inflammatory process would increase more than it’s required. In the future it will be possible to control artificially the transition of macrophages from M0 to M1-state with the help of itaconate. In other words it will constrain the intensity of inflammation. Impact of itaconate on macrophages is a quite delicate mechanism capable of providing high selectivity of regulation of the immune system."

Earlier the scientific community speculated about the functions and origin of itaconate. However, a new study shows that itaconate is a immunoregulator. To understand why itaconate reduces the activity of immune cells, scientists examined in details so called the Krebs cycle, or the tricarboxylic acid cycle in macrophages, which is a key step in cell respiration (the production process of vital substances and energy in the cell resulting from the oxidation of glucose) and is located at the intersection of many metabolical pathways. The scientists found two "bottlenecks" in this cycle. One can reverse reaction at the certain moment and send it in a different direction manipulating these bottlenecks.

The Krebs cycle is preceded by the transfer of signals between cells using oxygen sensitive ways.

Itaconate inhibits Sdh enzyme (succinate dehydrogenase), which not only ensures the functioning of the cycle of tricarboxylic acids but associates it with the signaling pathways.

Thus, itaconate affects both functions of Sdh enzyme and is capable to adjust Krebs cycle and signaling pathways. As a result of blocking the enzyme transport chain between macrophages is interrupted, and the process of their activation is slowing. "It is interesting that itaconate acts as an antioxidant and anti-inflammatory agent, -Vicky Lampropulu, lead author of the article, worker of the Laboratory of Maksim Artyomov at Washington University in St. Louis notes. - At the same time itaconate is safe as produced by the body. That makes it very attractive for using in the treatment of many pathologies occurring with excessive inflammation or oxidative effect, such as coronary heart disease, liver and kidney disease, metabolic disorders and may be even autoimmune diseases."

The researchers were able to demonstrate partially that itaconate could work as desired within living organisms. Experiments showed that the substance reduced damage in myocardial infarction in the case of mice, acting by the same mechanism of locking Sdh enzyme. However, to transfer the method on the human body the further studies are needed.


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