immune reactions, but little was known about their exact mechanism of action. However, researchers have now delved into the molecular details and discovered that glucocorticoids reprogram the metabolism of immune cells. This activation of the body’s natural inflammation ‘brakes’ provides new insights for the development of anti-inflammatory drugs with reduced side effects.
Immune reactions have always been a mystery in terms of how they work. However, a team of researchers from Charité — Universitätsmedizin Berlin, Uniklinikum Erlangen and Ulm University have delved into the molecular mechanism of action and discovered more details. According to their report in the journal Nature, the researchers found that glucocorticoids reprogram the metabolism of immune cells, which helps activate the body’s natural “brakes” on inflammation. This discovery paves the way for the development of anti-inflammatory agents that have fewer and less severe side effects.
The naturally occurring glucocorticoid cortisone is actuallyThe body produces cortisol, which is a stress hormone that helps the body respond to stress. Cortisol plays a role in sugar and fat metabolism, as well as other factors such as blood pressure, respiratory rate, and heart rate. At higher levels, it can also suppress the immune system, making it useful for medical purposes. Synthetic glucocorticoid derivatives, which are even more effective at reducing inflammation than natural cortisol, are commonly used to treat various immune-mediated inflammatory diseases. These medications are among the most commonly prescribed.of all.
Glucocorticoids not only impact genes, but also the body’s energy sources
However, medications based on glucocorticoids can have side effects, especially when taken at higher doses and for longer periods. These side effects are connected to the other effects of the body’s natural cortisol. They can include high blood pressure, osteoporosis, diabetes, and weight gain. In an effort to develop anti-inflammatory drugs with fewer and less severe side effects, a team of researchers led by Prof. Gerhard Krönke, director of the Department of Rheumatology and Clinical Immunology at Charité, has conducted a thorough investigation.The research aims to understand how glucocorticoids work to suppress the immune system. According to Krönke, previous knowledge suggested that glucocorticoids activate various genes in the body’s cells, but this does not fully explain their powerful immunosuppressive effect. The study reveals that glucocorticoids not only impact gene expression in immune cells, but also affect the mitochondria, which are vital to cell metabolism. This, in turn, is crucial to the anti-inflammatory effects of glucocorticoids.
The research team focused on macrophages, a type of immune cell that fights off intruders like viruses and bacteria. They wanted to see how these cells, taken from mice, would react to inflammatory stimuli in a lab setting and how they would respond to glucocorticoid treatment. The study found that glucocorticoids not only affected gene expression, but also had a significant impact on reversing changes in the immune cells.
Swords to plowshares
The article discusses the role of itaconate in regulating the anti-inflammatory effects of glucocorticoids. When macrophages are activated by inflammatory stimuli, their metabolism shifts to prepare for battle. Instead of producing energy, their mitochondria generate the necessary components to combat invaders. Glucocorticoids can reverse this process, deactivating the macrophages and turning their focus away from fighting. Itaconate is highlighted as a key player in this process.Itaconate is a substance with anti-inflammatory properties that is naturally produced by the body in its mitochondria. When macrophages are activated, they produce it to help reduce the inflammatory reaction. However, the production of itaconate requires enough fuel, which may not be available when the cell’s powerhouses are preparing for a fight. As a result, itaconate production stops after a period of time. This timing is effective for normal, short-term inflammation, but with a persistent inflammatory stimulus, the production of itaconate may be affected.An issue with shutting down itaconate production is that it removes the immune system’s ability to slow down, even when it’s working at full capacity, which can lead to chronic inflammation,” explained Dr. Jean-Philippe Auger, a scientist at the Department of Medicine 3 — Rheumatology and Immunology at Uniklinikum Erlangen and the study’s lead author. “This is where glucocorticoids come in. By reprogramming mitochondrial function, they increase itaconate formation in macrophages, restoring its anti-inflammatory effects.”
The quest for new active ingredients
Animal models were used to study astBy studying the relationship between itaconate and the anti-inflammatory effects of glucocorticoids in conditions like sepsis and rheumatoid arthritis, researchers found that the effectiveness of glucocorticoids is heavily reliant on itaconate. In animal studies, glucocorticoids had no impact on those unable to produce itaconate. Therefore, the question arises: instead of using glucocorticoids, could itaconate be administered directly to achieve the same immunosuppressant effect?
Unfortunately, itaconate is not an ideal candidate for use as an anti-inflammatory drug due to its instability and high reactivity, which could potentially lead to systemic side effects if administered. Additionally, researchers suspect that the production of itaconate may play a role in limiting inflammation and protecting cells from damage.The researchers found that the process of reprogramming mitochondrial metabolism in humans is more complex than in mice. Therefore, they plan to search for new synthetic compounds that can effectively reprogram immune cell mitochondrial metabolism like glucocorticoids, but with fewer and milder side effects.
