Cortisone and other related glucocorticoids are highly effective in inhibiting excessive immune responses. But before this, people knew very little about how they did it.
Now, in a new study, researchers from Berlin’s Charlotte Medical School, the University of Erlangen, and the University of Ulm have conducted a more detailed exploration of their molecular mechanisms of action. They report that glucocorticoids can reshape the metabolism of immune cells, activating the body’s natural “brakes” on inflammation. These findings lay the foundation for the development of anti-inflammatory drugs with smaller and lighter side effects.
The relevant research results were published online in the journal Nature, under the title “Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids”.
Cortisone, a member of the glucocorticoid family, is essentially a stress hormone that naturally exists in the human body in the form of cortisol. When the body is under pressure, it releases cortisol to optimize its response to stress. It regulates sugar and fat metabolism, while also affecting vital indicators such as blood pressure, respiratory rate, and heart rate. At higher doses, cortisol can also inhibit the activity of the immune system, making synthetic glucocorticoid derivatives widely used in the treatment of immune-mediated inflammatory diseases due to their excellent anti-inflammatory effects, becoming one of the most widely used drugs worldwide.
However, the effect of glucocorticoid is not limited to the gene level, but also profoundly changes the energy metabolism pathway of cells, which is also the root of its potential side effects. For example, long-term massive use may lead to hypertension, osteoporosis, diabetes, and weight gain.
To develop anti-inflammatory drugs with smaller and lighter side effects, Professor Gerhard Krönke, Director of the Department of Rheumatology and Clinical Immunology at the Chariot Medical School in Berlin, and his team conducted an in-depth analysis of the immunosuppressive mechanism of glucocorticoids.
Professor Krönke pointed out that although previous studies have revealed that glucocorticoids can activate numerous genes within cells, this does not fully elucidate their powerful immunosuppressive effects. Their new research confirms that glucocorticoids not only regulate gene expression in immune cells, but also directly affect the energy center of cells – mitochondria. This change in cellular metabolism is crucial for the anti-inflammatory effect of glucocorticoids.
In this new study, researchers focused on macrophages, which are immune cells responsible for clearing foreign invaders such as viruses and bacteria, and are also key factors in the occurrence of certain immune-mediated inflammatory diseases. Through experiments in a laboratory environment, they observed the response of macrophages extracted from experimental mice to inflammatory stimuli, as well as the effects of adding glucocorticoids. Research has found that in addition to regulating gene expression, glucocorticoids also significantly reverse cellular metabolic changes induced by inflammatory stimuli.
Krönke said, “When macrophages enter the ‘combat’ mode, they convert their cellular energy into combat. Their mitochondria no longer provide energy, but instead produce the components needed to strike invaders. Glucocorticoids reverse this process, turning off the ‘combat’ mode, which can be said to turn swords into plows. A small molecule called itaconate plays a particularly important role in it.”
Itaconic acid is a naturally occurring anti-inflammatory substance in the mitochondria of the human body. Macrophages produce this substance in the early stages of activation, so the inflammatory response will subside after a while. However, producing this natural immune “brake” requires sufficient fuel. When the cell’s energy factory is preparing for battle, the situation is no longer like this, so the production of itaconic acid will decrease to a stop after a while. For normal short-term inflammation, this timing is effective as the immune response has also weakened during this period.
Itaconic acid is a naturally occurring anti-inflammatory substance produced by human mitochondria. Macrophages produce a large amount of itaconic acid in the early stages of activation, ensuring that the inflammatory response gradually subsides at an appropriate time. However, under prolonged inflammatory stimulation, mitochondria are unable to provide sufficient fuel to maintain the production of itaconic acid due to the sustained combat mode, leading to a gradual decrease in their secretion until it stops, which may result in the persistence of chronic inflammation. Corticosteroids promote the generation of gluconic acid in macrophages by reprogramming mitochondrial function, thereby restoring their anti-inflammatory effects.
Researchers have used animal models of asthma and rheumatoid arthritis to confirm to what extent the anti-inflammatory effect of glucocorticoids depends on itaconic acid. Corticosteroids do not affect animals that cannot produce itaconic acid. So, if itaconic acid mediates the immunosuppressive effect of cortisone, wouldn’t it be enough to directly give animals’ itaconic acid instead of glucocorticoids?
Krönke explained, “Unfortunately, itaconic acid is not a particularly ideal anti-inflammatory drug because it is unstable and, due to its high reactivity, may have side effects if administered systemic. In addition, we believe that processes in the human body are more complex than those in mice. Therefore, we plan to search for new synthetic compounds that are as effective as glucocorticoids in reshaping mitochondrial metabolism in immune cells, but with smaller and less severe side effects.”
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Reference
Jean-Philippe Auger et al. Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids. Nature, 2024, doi:10.1038/s41586-024-07282-7.