Macrophages transition between three distinct stages during their lifetime: neutral (M0), pro-inflammatory (M1), and anti-inflammatory (M2). As expected, M1 macrophages are the type that arrives first at the scene of the crime, promoting inflammation to begin the immune attack on whatever pathogen has invaded the body. When a M1 macrophage becomes “overly diligent” though, numerous pathologies can result: cardiac ischemia, metabolic disorders, and even autoimmune diseases.
Too much inflammation is dangerous and leads to these diseases because of the absorption of energy resources required to keep the inflammatory pathway up and running. The new study looked at the transition process of macrophages between states, especially between their inactive and pro-inflammatory state. This is where itaconate comes into the picture, a natural metabolite released by macrophages whose role scientists have never quite understood – until now.
The researchers found that there seems to be a defined limit of the amount of itaconate that can be produced during the M0 – M1 transition, and as itaconate levels grow closer to the limit, macrophage activation to its pro-inflammatory state is designed to fail. “Itaconate sets the bar controlling M1 macrophage formation, said Alexey Sergushichev, one of the study’s authors.
Itaconate’s role within macrophage activation was finally realized when the researchers connected the metabolite to the bodily processes for producing energy from glucose oxidation: cellular respiration and the tricarboxylic acid cycle. An enzyme called succinate dehydrogenase (SDH) provides a component called fumarate to the tricarboxylic acid cycle. This is where the researchers saw itaconate interfering with energy production: itaconate blocks the enzyme entirely.
With the tricarboxylic acid cycle and cellular respiration halted without a necessary enzyme, macrophage activation to a pro-inflammatory state fails. In this way, itaconate acts as an anti-inflammatory agent, while it also acts as an antioxidant by blocking glucose oxidation.
The successful breakdown of itaconate and its role in macrophage activation is important for understanding how inflammatory diseases develop, as well as for how to treat them. Sergushichev believes that this new insight will lead to the ability of scientists to “artificially manipulate the transition of macrophages from M0 to M1, meaning the possibility of restraining inflammations.”
Sources: ITMO University, Current Opinion in Plant Biology